Qualification: 
Ph.D
cgmohan@aims.amrita.edu

Dr. Gopi Mohan C. is an Associate Professor at Amrita Center for Nanosciences and Molecular Medicine. He had graduated with Ph.D. from Banaras Hindu University, Varanasi, following which, had gained experience as Post-doctoral fellow from the Molecular Biophysics Unit at the Indian Institute of Science, Bangalore, and as Research Officer from the Department of Biology and Biochemistry, University of Bath, United Kingdom. Further, he had worked as an Associate Researcher of CNRS in Laboratoire de Cristallographie, and Modelisation des Materiaux Mineraux et Biologiques, University Henri Poincare, Nancy, France. 

Dr. Gopi Mohan has experience being a faculty at the National Institute of Pharmaceutical Education & Research (NIPER), Mohali, Punjab, from 2005 and serving there for six and half years. During his stay at NIPER, he has been instrumental in setting up different laboratories in the Pharmacoinformatics discipline. He was a recipient of Indo-Finland grant for computational biology, relating to drug development, and had visited University of Helsinki and University of Turku, to complete this collaborative bilateral program, successfully.

Dr. Gopi Mohan has supervised many Ph.D. and postgraduate students, and completed many research and industrial consultancy projects. He has published more than 70 research papers in refereed journals and is also an active reviewer of different international/national research journals, thesis and grants. Research interests of Dr. Gopi Mohan encompass Computational Biology & Structural Bioinformatics, Structure- Based Drug Design, Protein crystallography, and Nanoinformatics. Dr. Gopi Mohan is cited as an internationally recognized expert in the field of Structural Bioinformatics & Chemoinformatics by Synergix Ltd. United Kingdom.

Research

In silico drug discovery program is one of the prime objectives of the Bioinformatics and Computational Biology laboratory at the Centre for Nanosciences and Molecular Medicine. The center provides high quality teaching and research to M. Tech./MSc. and Ph.D. students to make them successful interdisciplinary application scientist in the future pre-clinical drug discovery program. Computational lab provides following functionality by integrating Bioinformatics and Chemoinformatics concepts:

  • Sequence alignment, Phylogeny, Molecular Graphics Visualization
  • Homology Modeling of Biomolecules, Druggable Target Identification & Validation
  • Computer Aided Drug Design: Molecular docking, Pharmacophore mapping, 2D and 3D QSAR, Virtual screening and Molecular dynamics simulations
  • Nanomaterial modeling, Nanotoxicity effect, Polymer-Drug interactions and Drug Delivery

Work carried at the center was internationally recognized and published peer reviewed research articles funded by the Department of Biotechnology, ICMR, DST, Govt. of India. Different commercial and freely available molecular modeling and design software was installed on Windows and Linux platforms and recently High-Performance Computing facility was also established.

At present working mainly in the area of Neurological disorder, Infections and Cancer disease causing druggable targets and Nanomaterial modeling and interaction studies.

Publications

Publication Type: Book Chapter

Year of Publication Title

2019

Dr. Gopi Mohan C., “Structural Bioinformatics- Applications in Preclinical Drug Discovery Process”, in The Challenges and Advances in Computational Chemistry and Physics series (Book title) Springer Nature Publisher, 2019.

2018

Dr. Gopi Mohan C., P., A. C., and Raja Biswas, “Impact of Target-Based Drug Design in Anti-bacterial Drug Discovery for the Treatment of Tuberculosis ”, in Structural Bioinformatics- Applications in Preclinical Drug Discovery Process”, The Challenges and Advances in Computational Chemistry and Physics series, Springer Nature Publisher, 2018.

2018

Dr. Gopi Mohan C., Melge, A. R., K, M., and Shantikumar V. Nair, “In Silico Modeling of FDA-Approved Drugs for Discovery of Anti-cancer Agents: A Drug Repurposing Approach ”, in “In Silico Drug Design: Repurposing Techniques and Methodologies, Elsevier Global Production, 2018.

2016

Dr. Gopi Mohan C. and Gupta, S., “QSAR Models towards Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease”, in Oncology: Breakthroughs in Research and Practice, 2016.[Abstract]


Alzheimer's Disease (AD) is a multifactorial neurological syndrome with the combination of aging, genetic, and environmental factors triggering the pathological decline. Interestingly, the importance of the Acetylcholinesterase (AChE) enzyme has increased due to its involvement in the ß-amyloid peptide fibril formation during AD pathogenesis. In silico technique, QSAR has proven its usefulness in pharmaceutical research for the design/optimization of new chemical entities. Further, QSAR method advanced the scope of rational drug design and the search for the mechanism of drug action. It is a well-established fact that the chemical and pharmaceutical effects of a compound are closely related to its physico-chemical properties, which can be calculated by various methods from the compound structure. This chapter focuses on different Quantitative Structure-Activity Relationship (QSAR) studies carried out for a variety of cholinesterase inhibitors for the treatment of AD. These predictive models will be potentially used for further designing better and safer drugs against AD. More »»

2011

Dr. Gopi Mohan C., Pandey, A., and Mungalpara, J., “Therapeutic Potential of N-Type Voltage-Gated Ca2+ Channel”, in Ion Channels and Their Inhibitors, S. Prakash Gupta, Ed. Berlin, Heidelberg: Springer Berlin Heidelberg, 2011, pp. 289–308.[Abstract]


Voltage-gated N-type Ca2+ channels (NCCs) play dominant roles in neuropathic pain and cerebral ischemia. Ion channel therapeutics for many pathophysiological conditions exists, which include: affective disorders, allergic disorders, autoimmune diseases, epilepsy, hypertension, insomnia, pain, anesthesia, anxiety, and stroke. Experimentally, it was well established that NCC inhibitory activity is essential for the treatment of chronic neuropathic pain and stroke. A major obstacle with these membrane proteins is that the atomic resolution experimental structures are not available to understand the mode of small molecule binding at its active sites. This article mainly focuses on Ca2+ channel blockers (CCBs), especially for NCCs, wherein lie some of the opportunities and advantages associated with these channels as drug target.

More »»

Publication Type: Journal Article

Year of Publication Title

2019

A. Choorakott Pushkaran, Vinod, V., Muralidharan Vanuopadath, Sudarslal S, Shantikumar V Nair, Vasudevan, A. Kumar, Dr. Raja Biswas, and Dr. Gopi Mohan C., “Combination of Repurposed Drug Diosmin with Amoxicillin-Clavulanic acid Causes Synergistic Inhibition of Mycobacterial Growth”, Scientific Reports, vol. 9, no. 1, 2019.[Abstract]


Effective therapeutic regimens for the treatment of tuberculosis (TB) are limited. They are comprised of multiple drugs that inhibit the essential cellular pathways in Mycobacterium tuberculosis (Mtb). The present study investigates an approach which enables a combination of Amoxicillin-Clavulanic acid (AMC) and a repurposed drug for its synergistic effect towards TB treatment. We identified Diosmin (DIO), by targeting the active site residues of L,D-transpeptidase (Ldt) enzymes involved in Mtb cell wall biosynthesis by using a structure-based drug design method. DIO is rapidly converted into aglycone form Diosmetin (DMT) after oral administration. Binding of DIO or DMT towards Ldt enzymes was studied using molecular docking and bioassay techniques. Combination of DIO (or DMT) and AMC exhibited higher mycobactericidal activity against Mycobacterium marinum as compared to individual drugs. Scanning electron microscopy study of M. marinum treated with AMC-DIO and AMC-DMT showed marked cellular leakage. M. marinum infected Drosophila melanogaster fly model showed an increased fly survival of 60% upon treatment with a combination of AMC and DIO (or DMT). Finally, the enhanced in vitro antimicrobial activity of AMC-DIO was validated against Mtb H37Ra and a MDR clinical isolate. Our results demonstrate the potential for AMC and DIO (or DMT) as a synergistic combination for the treatment of TB. © 2019, The Author(s).

More »»

2019

Serene Xavier, Dr. Gopi Mohan C., Shantikumar V Nair, Krishnakumar N. Menon, and Dr. Lakshmi Sumitra, “Generation of Humanized Single-chain Fragment Variable Immunotherapeutic against EGFR Variant III using Baculovirus Expression System and in vitro validation.”, Int J Biol Macromol, vol. 124, pp. 17-24, 2019.[Abstract]


Epidermal growth factor receptor variant III (EGFRvIII) is known to be specifically expressed in cancer cells and associated with tumor virulence. The receptor provides an opportunity for both specifically targeting the tumor cells as well as for potentially controlling and inhibiting tumor progression. In this study, humanized anti-EGFRvIII single-chain fragment variable (hscFv) was expressed in insect cell culture system to accommodate post-translational glycosylations crucial for the fragment stability and efficacy. Target specific binding of the developed fragment to EGFRvIII expressing cell lines and EGFRvIII positive glioblastoma patient samples was evaluated by immunocytochemistry and immunohistochemistry respectively. Downstream intracellular signaling mechanisms related to the action of the developed antibody fragment on growth/metabolism of the cell was evaluated in U87-EGFRvIII human glioblastoma cell lines. It was observed that the hscFv bound specifically to EGFRvIII in mutant expressing cells. Functionally, hscFv was found to confer anti-proliferative properties in EGFRvIII expressing cell lines by downregulating phosphorylation of EGFR/EGFRvIII, Lyn, PI3K and GLUT3 involved in proliferation and metabolism. This study demonstrated the significance of hscFv as a potential immunotherapeutic agent as well as a targeting agent for specific delivery of drugs to EGFRvIII expressing cancer cells.

More »»

2019

A. C. P, Subhramanian, S., Sizochenko, N., Melge, A. R., Leszczynski, J., and Dr. Gopi Mohan C., “Multiple e-Pharmacophore Modeling to Identify a Single Molecule that could Target Both Streptomycin and Paromomycin Binding sites for 30S Ribosomal Subunit Inhibition”, J Biomol Struct Dyn, vol. 37, no. 6, pp. 1582-1596, 2019.[Abstract]


<p>The bacterial ribosome is an established target for anti-bacterial therapy since decades. Several inhibitors have already been developed targeting both defined subunits (50S and 30S) of the ribosome. Aminoglycosides and tetracyclines are two classes of antibiotics that bind to the 30S ribosomal subunit. These inhibitors can target multiple active sites on ribosome that have a complex structure. To screen putative inhibitors against 30S subunit of the ribosome, the crystal structures in complex with various known inhibitors were analyzed using pharmacophore modeling approach. Multiple active sites were considered for building energy-based three-dimensional (3D) pharmacophore models. The generated models were validated using enrichment factor on decoy data-set. Virtual screening was performed using the developed 3D pharmacophore models and molecular interaction towards the 30S ribosomal unit was analyzed using the hits obtained for each pharmacophore model. The hits that were common to both streptomycin and paromomycin binding sites were identified. Further, to predict the activity of these hits a robust 2D-QSAR model with good predictive ability was developed using 16 streptomycin analogs. Hence, the developed models were able to identify novel inhibitors that are capable of binding to multiple active sites present on 30S ribosomal subunit.</p>

More »»

2018

A. R. Melge, Kumar, L. G., Pavithran, K., Shantikumar V Nair, Dr. Manzoor K., and Dr. Gopi Mohan C., “Predictive Models for Designing Potent Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia for Understanding its Molecular Mechanism of Resistance by Molecular Docking and Dynamics Simulations”, Journal of Biomolecular Structure and Dynamics, 2018.[Abstract]


BCR-ABL fusion protein drives chronic myeloid leukemia (CML) which constitutively activates tyrosine kinase involved in the initiation and maintenance of CML phenotype. Ponatinib, an oral drug, was discovered as an efficient BCR-ABL inhibitor by addressing imatinib drug resistance arising due to the point mutations at its active sites. In this study, 44 BCR-ABL kinase inhibitors, which are derivatives of ponatinib, were used to develop a robust two-dimensional quantitative structure–activity relationship (2D-QSAR) and 3D-Pharmacophore models by dividing dataset into 32 training sets and 12 test set molecules. 2D-QSAR model was developed using Genetic Function Approximation (GFA) algorithm consisting of four types of information-rich molecular descriptors, electrotopological (ES_Count_aasN and ES_Sum_aaaC), electronic (Dipole_X), spatial (PMI_Y) and thermodynamic (LogD), primarily contributing to BCR-ABL kinase inhibitory activity. For the best 2D-QSAR model, the statistics were R 2 = 0.8707, R 2 pred = 0.8142 and N = 32 for the training set molecules. Phase module of Schrödinger suit was employed for 3D-Pharmacophore model development showing five different pharmacophoric features–ADHHPRR with good R 2 of 0.9629, F of 175.3, Q 2 of 0.645 and root-mean-square error (RMSE) of 0.214 that are essential for an effective BCR-ABL kinase inhibition. These two models were further validated by cross-validation, test set predictions, enrichment factor calculations and predictions based on the external dataset. The molecular mechanism of resistance arising due to gate keeper mutation T315I of ABL kinase in complex with its inhibitors was also studied using molecular docking and molecular dynamics simulations. Our developed models predicted key chemical features for designing potent inhibitors against BCR-ABL kinase activity and its resistance mechanism to CML disease therapy. Communicated by Ramaswamy H. Sarma. © 2019, © 2019 Informa UK Limited, trading as Taylor &amp; Francis Group.

More »»

2018

A. Baldi, Mooij, L., Palmisano, V., Schreuders, H., Dr. Gopi Mohan C., Kooi, B. J., Dam, B., and Griessen, R., “Elastic versus Alloying Effects in Mg-Based Hydride Films”, Phys. Rev. Lett., vol. 121, p. 255503, 2018.

2018

V. Aparna, Melge, A. Rohit, Rajan, V. K., Raja Biswas, Dr. Jayakumar Rangasamy, and Dr. Gopi Mohan C., “Carboxymethylated ɩ-carrageenan Conjugated Amphotericin B loaded Gelatin Nanoparticles for Treating Intracellular Candida Glabrata Infections”, International Journal of Biological Macromolecules, vol. 110, pp. 140 - 149, 2018.[Abstract]


Intercellular Candida glabrata infections are difficult to treat due to poor penetration of drugs into the fungal niche. Delivering amphotericin B (Amp B) into the macrophages where the pathogen inhabits is an effective solution. We are studying the macrophage targeting proficiency of ɩ-carrageenan for the delivery of Amp B using gelatin A nanoparticles (GNPs). The choice of gelatin A was the outcome of in silico inspections where the amino functionalized polymer having the best docking score with Amp B was selected. We prepared a sustained release formulation of amp B loaded carboxymethyl ɩ-carrageenan conjugated gelatin nanoparticles (CMC-Amp B-GNPs) with size 343±12nm and −25±5.3mV zeta potential. The formulations were found to be stable, biocompatible and non-haemolytic. Flow cytometry analysis showed 3 fold higher uptake of CMC-GNPs compared to the GNPs by RAW 264.7 cells. CMC-Amp B-GNPs showed enhanced antifungal activity than bare Amp B and Amp B-GNPs.

More »»

2018

S. Nithya, Nimal, T. R., Baranwal, G., Suresh, M. K., C.P., A., V. Kumar, A., Dr. Gopi Mohan C., Dr. Jayakumar Rangasamy, and Dr. Raja Biswas, “Preparation, Characterization and Efficacy of Lysostaphin-chitosan Gel Against Staphylococcus Aureus”, International Journal of Biological Macromolecules, 2018.[Abstract]


Lysostaphin (LST) is a bacteriocin that cleaves within the pentaglycine cross bridge of Staphylococcus aureus peptidoglycan. Previous studies have reported the high efficiency of LST even against multi drug resistant S. aureus including methicillin resistant S. aureus (MRSA). In this study, we have developed a new chitosan based hydrogel formulation of LST to exploit its anti-staphylococcal activity. The atomic interactions of LST with chitosan were studied by molecular docking studies. The rheology and the antibacterial properties of the developed LSTC gel were evaluated. The developed LST containing chitosan hydrogel (LSTC gel) was flexible, flows smoothly and remains stable at physiological temperature. The in vitro studies by agar well diffusion and ex vivo studies in porcine skin model exhibited a reduction in S. aureus survival by 3 Log10CFU/mL in the presence of LSTC gel. The cytocompatibility of the gel was tested in vitro using macrophage RAW 264.7 cell line and in vivo in Drosophila melanogaster. A gradual disruption of S. aureus biofilms with the increase of LST concentrations in the LSTC gel was observed which was confirmed by SEM analysis. We conclude that LSTC gel could be highly effectual and advantageous over antibiotics in treating staphylococcal-topical and biofilm infections.

More »»

2018

A. R. Melge, Prakash, O., S, S., Dr. Raja Biswas, Lalitha Biswas, and Dr. Gopi Mohan C., “Structure-Function Studies of Prothrombin Amrita, a Dysfunctional Prothrombin Characterized by Point Mutation at Arg553 → Gln”, International Journal of Biological Macromolecules, 2018.[Abstract]


A dysfunctional prothrombin gene characterized by novel point mutation at Arg553 to Gln residue in Deep vein thrombosis (DVT) patient which we designated as "Prothrombin Amrita" was previously reported from our lab. The mutation occurred at nucleotide 20030 in exon 14 and was confirmed by restriction enzyme digestion. Arg553 has been reported as one of the key residues for the binding of cofactor Na+ ion in the thrombin protein. Structural analysis revealed the molecular mechanism behind the coagulant form of thrombin due to point Arg553Gln mutation near the cofactor Na+ ion region. Molecular electrostatic potential maps and molecular dynamics (MD) simulation of the wild type and mutated thrombin showed the key role played by the Na+ ion for its coagulant mechanism by analysing the charge distribution and nature of the hydrogen bonding at the mutated region of interest. We observed maintenance of the fast or procoagulant form of dysfunctional prothrombin due to changes in the charge distribution by this mutation and thereby also keeping strong hydrogen bonding network revealed by MD simulation between prothrombin and Na+ ion. This molecular mechanism might be the main cause for DVT in patients with this dysfunctional prothrombin gene.

More »»

2018

F. Basheer, Melge, A. R., Sasidharan, A., Shantikumar V Nair, Dr. Manzoor K., and Dr. Gopi Mohan C., “Computational Simulations and Experimental Validation of Structure- Physicochemical Properties of Pristine and Functionalized Graphene: Implications for Adverse Effects on p53 Mediated DNA Damage Response”, International Journal of Biological Macromolecules, vol. 110, pp. 540-549, 2018.[Abstract]


<p>Recent reports indicated DNA damaging potential of few-layer graphene in human cell systems. Here, we used computational technique to understand the interaction of both pristine (pG) or carboxyl functionalized graphene (fG) of different sizes (1, 6, and 10nm) with an important DNA repair protein p53. The molecular docking study revealed strong interaction between pG and DNA binding domains (DBD) of p53 with binding free energies (BE) varying from -12.0 (1nm) to -34 (6nm)kcal/mol, while fG showed relatively less interaction with BE varying from -6.7 (1nm) to -11.1 (6nm)kcal/mol. Most importantly, pG or fG bound p53-DBDs could not bind to DNA. Further, microarray analysis of human primary endothelial cells revealed graphene intervention on DNA damage and its structure-properties effect using comet assay studies. Thus, computational and experimental results revealed the structure-physicochemical property dependent adverse effects of graphene in DNA repair protein p53.</p>

More »»

2017

P. S. Panicker, Melge, A. R., Dr. Lalitha Biswas, Keechilat, P., and Dr. Gopi Mohan C., “Epidermal Growth Factor Receptor (EGFR) Structure-based Bioactive Pharmacophore Models for Identifying Next-generation Inhibitors Against Clinically relevant EGFR Mutations”, Chemical Biology & Drug Design, vol. 90, pp. 629-636, 2017.[Abstract]


Present work elucidates identification of next generation inhibitors for clinically relevant mutations of epidermal growth factor receptor (EGFR) using structure-based bioactive pharmacophore modeling followed by virtual screening (VS) techniques. Three-dimensional (3D) pharmacophore models of EGFR and its different mutants were generated. This includes seven 3D pharmacophoric points with three different chemical features (descriptors), that is, one hydrogen bond donor, three hydrogen bond acceptors and three aromatic rings. Pharmacophore models were validated using decoy dataset, Receiver operating characteristic plot, and external dataset compounds. The robust, bioactive 3D e-pharmacophore models were then used for VS of four different small compound databases: FDA approved, investigational, anticancer, and bioactive compounds collections of Selleck Chemicals. CUDC101 a multitargeted kinase inhibitor showed highest binding free energy and 3D pharmacophore fit value than the well known EGFR inhibitors, Gefitinib and Erlotinib. Further, we obtained ML167 as the second best hit on VS from bioactive database showing high binding energy and pharmacophore fit value with respect to EGFR receptor and its mutants. Optimistically, presented drug discovery based on the computational study serves as a foundation in identifying and designing of more potent EGFR next-generation kinase inhibitors and warrants further experimental studies to fight against lung cancer.

More »»

2017

S. M, S, U., Dr. Gopi Mohan C., B, S., IK, P., and R, J., “In vivo evaluation of cetuximab-conjugated poly(γ-glutamic acid)-docetaxel nanomedicines in EGFR-overexpressing gastric cancer xenografts.”, International Journal of Nanomedicine, 2017.[Abstract]


Epidermal growth factor receptor (EGFR), upregulated in gastric cancer patients, is an oncogene of interest in the development of targeted cancer nanomedicines. This study demonstrates in silico modeling of monoclonal antibody cetuximab (CET MAb)-conjugated docetaxel (DOCT)-loaded poly(γ-glutamic acid) (γ-PGA) nanoparticles (Nps) and evaluates the in vitro/in vivo effects on EGFR-overexpressing gastric cancer cells (MKN-28). Nontargeted DOCT-γ-PGA Nps (NT Nps: 110±40 nm) and targeted CET MAb-DOCT-γ-PGA Nps (T Nps: 200±20 nm) were prepared using ionic gelation followed by 1-Ethyl-3-(3-dimethyl aminopropyl)carbodiimide-N-Hydoxysuccinimide (EDC-NSH) chemistry. Increased uptake correlated with enhanced cytotoxicity induced by targeted Nps to EGFR +ve MKN-28 compared with nontargeted Nps as evident from MTT and flow cytometric assays. Nanoformulated DOCT showed a superior pharmacokinetic profile to that of free DOCT in Swiss albino mice, indicating the possibility of improved therapeutic effect in the disease model. Qualitative in vivo imaging showed early and enhanced tumor targeted accumulation of CET MAb-DOCT-γ-PGA Nps in EGFR +ve MKN-28-based gastric cancer xenograft, which exhibited efficient arrest of tumor growth compared with nontargeted Nps and free DOCT. Thus, actively targeted CET MAb-DOCT-γ-PGA Nps could be developed as a substitute to conventional nonspecific chemotherapy, and hence could become a feasible strategy for cancer therapy for EGFR-overexpressing gastric tumors.

More »»

2017

M. Chatterjee, Pushkaran, A. Choorakott, Vasudevan, A. Kumar, Krishnakumar N. Menon, Dr. Raja Biswas, and Dr. Gopi Mohan C., “Understanding the Adhesion Mechanism of Mucin Binding domain from Lactobacillus fermentum and its Role in Enteropathogen Exclusion.”, Int J Biol Macromol, vol. 110, pp. 598-607, 2017.[Abstract]


<p>Lactobacillus species possesses surface exposed Mucin Binding Protein (MucBP) which plays a role in adhesion to gastrointestinal mucin. MucBP contains one or more mucin binding domain (MBD), the functionality of which has yet not been characterized thoroughly. Here, we have characterized a 93-amino acid MBD (MBD) of MucBP (LAF_0673) from Lactobacillus fermentum. Multiple sequence alignment of L. fermentum MBD exhibited ∼60% sequence homology with MBDs from other Lactobacillus species. Further, we cloned, expressed and purified MBD from Escherichia coli as N-terminal histidine-tagged protein (6X His-MBD). The purified MBD was able to bind to mucin and showed strong affinity towards the terminally expressed mucin glycans viz. N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), Galactose (Gal), and Sialic acid (N-acetylneuraminic acid; Neu5Ac). In silico experiments further confirmed the interaction between homology modeled MBD to mucin glycans through hydrogen-bonding with its surface amino acid residues Ser, Pro, Ile, Tyr and Ala. We also have demonstrated that MBD was able to inhibit the adhesion of enteric pathogens, including E. coli, Salmonella Paratyphi A, Shigella sonnei and Proteus vulgaris to mucin. Our results suggested that L. fermentum MBD is a functionally sufficient unit to act as an adhesin and to protect from invading enteric pathogens.</p>

More »»

2017

M. Chatterjee, D'Morris, S., Paul, V., Warrier, S., Vasudevan, A. Kumar, Muralidharan Vanuopadath, Nair, S. Sadasivan, Dr. Bindhu Paul, Dr. Gopi Mohan C., and Dr. Raja Biswas, “Mechanistic Understanding of Phenyllactic Acid Mediated Inhibition of Quorum Sensing and Biofilm Development in Pseudomonas Aeruginosa”, Appl Microbiol Biotechnol, vol. 101, no. 22, pp. 8223-8236, 2017.[Abstract]


Pseudomonas aeruginosa depends on its quorum sensing (QS) system for its virulence factors' production and biofilm formation. Biofilms of P. aeruginosa on the surface of indwelling catheters are often resistant to antibiotic therapy. Alternative approaches that employ QS inhibitors alone or in combination with antibiotics are being developed to tackle P. aeruginosa infections. Here, we have studied the mechanism of action of 3-Phenyllactic acid (PLA), a QS inhibitory compound produced by Lactobacillus species, against P. aeruginosa PAO1. Our study revealed that PLA inhibited the expression of virulence factors such as pyocyanin, protease, and rhamnolipids that are involved in the biofilm formation of P. aeruginosa PAO1. Swarming motility, another important criterion for biofilm formation of P. aeruginosa PAO1, was also inhibited by PLA. Gene expression, mass spectrometric, functional complementation assays, and in silico data indicated that the quorum quenching and biofilm inhibitory activities of PLA are attributed to its ability to interact with P. aeruginosa QS receptors. PLA antagonistically binds to QS receptors RhlR and PqsR with a higher affinity than its cognate ligands N-butyryl-L-homoserine lactone (C-HSL) and 2-heptyl-3,4-dihydroxyquinoline (PQS; Pseudomonas quinolone signal). Using an in vivo intraperitoneal catheter-associated medaka fish infection model, we proved that PLA inhibited the initial attachment of P. aeruginosa PAO1 on implanted catheter tubes. Our in vitro and in vivo results revealed the potential of PLA as anti-biofilm compound against P. aeruginosa.

More »»

2017

N. K. Gayathri, Aparna, V., Maya, S., Biswas, R., Jayakumar, R., and Dr. Gopi Mohan C., “Preparation, Characterization, drug Release and Computational Modelling Studies of Antibiotics Loaded Amorphous Chitin Nanoparticles.”, Carbohydr Polym, vol. 177, pp. 67-76, 2017.[Abstract]


<p>We present a computational investigation of binding affinity of different types of drugs with chitin nanocarriers. Understanding the chitn polymer-drug interaction is important to design and optimize the chitin based drug delivery systems. The binding affinity of three different types of anti-bacterial drugs Ethionamide (ETA) Methacycline (MET) and Rifampicin (RIF) with amorphous chitin nanoparticles (AC-NPs) were studied by integrating computational and experimental techniques. The binding energies (BE) of hydrophobic ETA, hydrophilic MET and hydrophobic RIF were -7.3kcal/mol, -5.1kcal/mol and -8.1kcal/mol respectively, with respect to AC-NPs, using molecular docking studies. This theoretical result was in good correlation with the experimental studies of AC-drug loading and drug entrapment efficiencies of MET (3.5±0.1 and 25± 2%), ETA (5.6±0.02 and 45±4%) and RIF (8.9±0.20 and 53±5%) drugs respectively. Stability studies of the drug encapsulated nanoparticles showed stable values of size, zeta and polydispersity index at 6°C temperature. The correlation between computational BE and experimental drug entrapment efficiencies of RIF, ETA and MET drugs with four AC-NPs strands were 0.999 respectively, while that of the drug loading efficiencies were 0.854 respectively. Further, the molecular docking results predict the atomic level details derived from the electrostatic, hydrogen bonding and hydrophobic interactions of the drug and nanoparticle for its encapsulation and loading in the chitin-based host-guest nanosystems. The present results thus revealed the drug loading and drug delivery insights and has the potential of reducing the time and cost of processing new antibiotic drug delivery nanosystem optimization, development and discovery.</p>

More »»

2017

S. Vijayrajratnam, Pushkaran, A. Choorakott, Balakrishnan, A., Vasudevan, A. Kumar, Dr. Raja Biswas, and Dr. Gopi Mohan C., “Understanding the Molecular Differential Recognition of Muramyl Peptide Ligands by LRR Domains of Human NOD Receptors.”, Biochem J, vol. 474, no. 16, pp. 2691-2711, 2017.[Abstract]


<p>Human nucleotide-binding oligomerization domain proteins, hNOD1 and hNOD2, are host intracellular receptors with C-terminal leucine-rich repeat (LRR) domains, which recognize specific bacterial peptidoglycan (PG) fragments as their ligands. The specificity of this recognition is dependent on the third amino acid of the stem peptide of the PG ligand, which is usually -diaminopimelic acid (DAP) or l-lysine (l-Lys). Since the LRR domains of hNOD receptors had been experimentally shown to confer the PG ligand-sensing specificity, we developed three-dimensional structures of hNOD1-LRR and the hNOD2-LRR to understand the mechanism of differential recognition of muramyl peptide ligands by hNOD receptors. The hNOD1-LRR and hNOD2-LRR receptor models exhibited right-handed curved solenoid shape. The hot-spot residues experimentally proved to be critical for ligand recognition were located in the concavity of the NOD-LRR and formed the recognition site. Our molecular docking analyses and molecular electrostatic potential mapping studies explain the activation of hNOD-LRRs, in response to effective molecular interactions of PG ligands at the recognition site; and conversely, the inability of certain PG ligands to activate hNOD-LRRs, by deviations from the recognition site. Based on molecular docking studies using PG ligands, we propose few residues - G825, D826 and N850 in hNOD1-LRR and L904, G905, W931, L932 and S933 in hNOD2-LRR, evolutionarily conserved across different host species, which may play a major role in ligand recognition. Thus, our integrated experimental and computational approach elucidates the molecular basis underlying the differential recognition of PG ligands by hNOD receptors.</p>

More »»

2016

S. Vijayrajratnam, Pushkaran, A. Choorakott, Balakrishnan, A., Vasudevan, A., Biswas, R., and Dr. Gopi Mohan C., “Bacterial Peptidoglycan with Amidated meso -diaminopimelic acid Evades NOD1 Recognition: An insight on NOD1 Structure-Recognition Study”, Biochemical Journal, 2016.[Abstract]


Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an intracellular pattern recognition receptor that recognizes bacterial peptidoglycan (PG) containing meso -diaminopimelic acid ( meso DAP) and activates the innate immune system. Interestingly, few pathogenic and commensal bacteria modify their PG stem peptide by amidation of meso DAP ( meso DAPNH2). In this study, NOD1 stimulation assays were performed using bacterial PG containing meso DAP (PGDAP) and meso DAPNH2 (PGDAPNH2) to understand the differences in their biomolecular recognition mechanism. PGDAP was effectively recognized, while PGDAPNH2 showed reduced recognition by NOD1 receptor. Re-stimulation of the NOD1 receptor which was initially stimulated with PGDAP, using PGDAPNH2, did not show any further NOD1 activation levels than PGDAP alone. But NOD1 receptor, initially stimulated with PGDAPNH2 responded effectively to re-stimulation with PGDAP. The biomolecular structure-recognition relationship of the ligand sensing LRR domain of human NOD1 (NOD1-LRR) with PGDAP and PGDAPNH2 was studied by different computational techniques to further understand the molecular basis of our experimental observations. The D-Glu- meso DAP motif of GMTPDAP, which is the minimum essential motif for NOD1 activation, was found involved in specific interactions at the recognition site, but the interactions of the corresponding D-Glu- meso DAP motif of PGDAPNH2 occurs away from the recognition site of NOD1 receptor. Hot-spot residues identified for effective PG recognition by NOD1-LRR include W820, G821, D826 and N850, which are evolutionarily conserved across different host species. These integrated results thus successfully provided the atomic level and biochemical insight on how PGs containing meso DAPNH2 evade NOD1-LRR receptor recognition.

More »»

2016

T. Gandhi, Melge, A. R., and Dr. Gopi Mohan C., “In Silico Identification of T-type Calcium Channel Blockers: A ligand-based Pharmacophore Mapping Approach”, Journal of Advanced Research, vol. 7, pp. 931-944, 2016.[Abstract]


Limited progress has been made in the quest to identify both selective and non-toxic T-type calcium channel blocking compounds. The present research work was directed toward slaking the same by identifying the selective three dimensional (3D) pharmacophore map for T-type calcium channel blockers (CCBs). Using HipHop module in the CATALYST 4.10 software, both selective and non-selective HipHop pharmacophore maps for T-type CCBs were developed to identify its important common pharmacophoric features. HipHop pharmacophore map of the selective T-type CCBs contained six different chemical features, namely ring aromatic (R), positive ionizable (P), two hydrophobic aromatic (Y), hydrophobic aliphatic (Z), hydrogen bond acceptor (H) and hydrogen bond donor (D). However, non-selective T-type CCBs contain all the above mentioned features except ring aromatic (R). The present ligand-based pharmacophore mapping approach could thus be utilized in classifying selective vs. non-selective T-type CCBs. Further, the model can be used for virtual screening of several small molecule databases.

More »»

2016

S. Patil, Tyagi, A., Jose., J., Krishnakumar N. Menon, and Dr. Gopi Mohan C., “Integration of Common Feature Pharmacophore Modeling and in Vitro Study to Identify Potent AChE Inhibitors”, Medicinal Chemistry Research, vol. 25, pp. 2965–2975, 2016.[Abstract]


Alzheimer's disease is a progressive neurodegenerative disorder arising due to genetic and non-genetic causes. One of the major therapies adapted for symptomatic Alzheimer's disease is by targeting acetylcholinesterase enzyme based on the cholinergic hypothesis. Acetylcholinesterase is a substrate-specific enzyme that degrades the neuro-transmitter acetylcholine. An optimum level of acetylcholine should be maintained in the brain for its proper function. In order to identify potent and selective acetylcholinesterase inhibitors we adopted an integrated in silico and bioassay methodologies. In silico approach involves creating chemical features based 3D-pharmacophore models using AChE specific inhibitors. This model was then used for sequential virtual screening from the small molecule databases. Finally, five molecules were selected on the basis of the best docking scores and pharmacokinetics properties. These molecules were subjected to docking analysis with the recently solved crystal structure of human acetylcholinesterase enzyme, in order to reveal its binding mode and interactions at the dual binding sites of the enzyme. The acetylcholinesterase enzyme inhibitory activity of these five lead molecules was further assessed by in-vitro analysis.

More »»

2016

P. Geetha, Sivaram, A. J., Dr. Jayakumar Rangasamy, and Dr. Gopi Mohan C., “Integration of in silico modeling, prediction by binding energy and experimental approach to study the amorphous chitin nanocarriers for cancer drug delivery”, Carbohydrate Polymers, vol. 142, pp. 240-249, 2016.[Abstract]


In silico modeling of the polymer-drug nanocarriers have now days became a powerful virtual screening tool for the optimization of new drug delivery systems. The interactions between amorphous chitin nanoparticles (AC-NPs) with three different types of anti-cancer drugs such as curcumin, docetaxel and 5-flurouracil were studied by integration of computational and experimental techniques. The drug entrapment and drug loading efficiency of these three drugs with AC-NPs were (98 ± 1%), (77 ± 2%), and (47 ± 12%), respectively. Further, cytotoxicity and cellular uptake studies of drug loaded AC-NPs on Gastric adenocarcinoma (AGS) cells showed enhanced drug uptake and cancer cell death. In silico binding energy (BE) between AC-NPs with these anti-cancer drugs were studied by molecular docking technique. Computational drug's BEs are in excellent agreement with experimental AC-NPs drug loading (R2 = 0.9323) and drug entrapment (R2 = 0.9741) efficiencies. Thus, present integrated study revealed significant insight on chemical nature, strength, and putative interacting sites of anti-cancer drugs with AC-NPs. © 2016 Elsevier Ltd. All rights reserved.

More »»

2016

M. Chatterjee, Anju, C. P., Biswas, L., V. Kumar, A., Dr. Gopi Mohan C., and Dr. Raja Biswas, “Antibiotic Resistance in Pseudomonas Aeruginosa and Alternative Therapeutic Options”, International Journal of Medical Microbiology, vol. 306, pp. 48 - 58, 2016.[Abstract]


Pseudomonas aeruginosa is a leading cause of nosocomial infections and is responsible for ∼10% of all hospital-acquired infections worldwide. It continues to pose a therapeutic challenge because of the high rate of morbidity and mortality associated with it and the possibility of development of drug resistance during therapy. Standard antibiotic regimes against P. aeruginosa are increasingly becoming ineffective due to the rise in drug resistance. With the scope for developing new antibiotics being limited, alternative treatment options are gaining more and more attention. A number of recent studies reported complementary and alternative treatment options to combat P. aeruginosa infections. Quorum sensing inhibitors, phages, probiotics, anti-microbial peptides, vaccine antigens and antimicrobial nanoparticles have the potential to act against drug resistant strains. Unfortunately, most studies considering alternative treatment options are still confined in the pre-clinical stages, although some of these findings have tremendous potential to be turned into valuable therapeutics. This review is intended to raise awareness of several novel approaches that can be considered further for combating drug resistant P. aeruginosa infections. © 2015 Elsevier GmbH.

More »»

2015

A. C. Pushkaran, Nataraj, N., Nair, N., Götz, F., Dr. Raja Biswas, and Dr. Gopi Mohan C., “Understanding the Structure–Function Relationship of Lysozyme Resistance in Staphylococcus aureus by Peptidoglycan O-Acetylation Using Molecular Docking, Dynamics, and Lysis Assay”, Journal of Chemical Information and Modeling, vol. 55, pp. 760-770, 2015.[Abstract]


Lysozyme is an important component of the host innate defense system. It cleaves the β-1,4 glycosidic bonds between N-acetylmuramic acid and N-acetylglucosamine of bacterial peptidoglycan and induce bacterial lysis. Staphylococcus aureus (S. aureus), an opportunistic commensal pathogen, is highly resistant to lysozyme, because of the O-acetylation of peptidoglycan by O-acetyl transferase (oatA). To understand the structure–function relationship of lysozyme resistance in S. aureus by peptidoglycan O-acetylation, we adapted an integrated approach to (i) understand the effect of lysozyme on the growth of S. aureus parental and the oatA mutant strain, (ii) study the lysozyme induced lysis of exponentially grown and stationary phase of both the S. aureus parental and oatA mutant strain, (iii) investigate the dynamic interaction mechanism between normal (de-O-acetylated) and O-acetylated peptidoglycan substrate in complex with lysozyme using molecular docking and molecular dynamics simulations, and (iv) quantify lysozyme resistance of S. aureus parental and the oatA mutant in different human biological fluids. The results indicated for the first time that the active site cleft of lysozyme binding with O-acetylated peptidoglycan in S. aureus was sterically hindered and the structural stability was higher for the lysozyme in complex with normal peptidoglycan. This could have conferred reduced survival of the S. aureus oatA mutant in different human biological fluids. Consistent with this computational analysis, the experimental data confirmed decrease in the growth, lysozyme induced lysis, and lysozyme resistance, due to peptidoglycan O-acetylation in S. aureus.

More »»

2014

V. Kumar, Bansal, G., Patel, J., and Dr. Gopi Mohan C., “Structure–Function Prediction of $\alpha$2A-, $\alpha$2B-, and $\alpha$2C-Adrenoceptors using Homology Model Assisted Antagonist Binding Study”, Medicinal Chemistry Research, vol. 23, pp. 735–746, 2014.[Abstract]


$\alpha$2A-, $\alpha$2B-, and $\alpha$2C-adrenoceptors belong to the rhodopsin-like G-protein coupled receptors family. They are integral membrane proteins typified by a bundle of seven transmembrane helices. 50&nbsp;{%} of the currently available drugs in the market target G-protein coupled receptors. Crystal structure of $\alpha$2A-, $\alpha$2B-, and $\alpha$2C-adrenoceptors are not yet solved. We performed homology modeling of the human $\alpha$2A-, $\alpha$2B-, and $\alpha$2C-adrenoceptor subtypes based on the crystal structure of the $\beta$2-adrenergic receptor. Molecular docking studies of five different antagonists toward these receptors revealed receptor subtype selectivity, and which in turn potentially guide in the rational design of subtype selective antagonists.

More »»

2014

P. Anjali, Vani, R., Sonia, T. S., Nair, AaSreekumara, Ramakrishna, S., Ranjusha, R., Subramanian, K. R. V., Sivakumar, N., Dr. Gopi Mohan C., Nair, S. V., and Balakrishnan, A., “Cerium Doped NiO Nanoparticles: A Novel Electrode Material for High Performance Pseudocapacitor Applications”, Science of Advanced Materials, vol. 6, pp. 94-101, 2014.[Abstract]


The present study demonstrates a novel electrodeposition approach by which Ce3+ doped NiO nanoparticles coated on titanium foils can be processed into a high surface area electrode for rechargeable energy storage applications. A detailed study has been performed to elucidate how cerium substitution doping and redox reaction behaviors underlying these electrodes impact the cyclic and capacitive behavior of the electrode. These nanoparticles were synthesized via molten salt technique and exhibited particle size of &nbsp;65 nm. From the analysis of the relevant electrochemical parameters, an intrinsic correlation between the substitutional doping amount, capacitance and the internal resistance has been deduced and explained on the basis of relative contributions from the faradic properties of the Ce3+ doped NiO nanoparticles in different electrolytes of varied concentrations. These thin film electrodes exhibited specific mass capacitance value as high as 1500 Fg-1 and 1077 Fg-1 (1 Ag-1) measured from cyclic voltammetry and charge discharge curves respectively, which was found to be 5 times higher than the pristine NiO nanoparticles with a capacitance retention of &gt;70% at the end of 2000th cycle. Further, a working model button cell employing these rechargeable electrodes is also demonstrated exhibiting an energy and power density of 92 Wh Kg-1 and 10 kW Kg-1, respectively. It has been shown that electrodes based on such nanoparticles can allow significant room for improvement in the cyclic stability and performance of a hybrid capacitor/battery system.

More »»

2014

D. Karlsson, Fallarero, A., Shinde, P., Anju, C. P., Busygin, I., Leino, R., Dr. Gopi Mohan C., and Vuorela, P., “Chemical modifications of cinchona alkaloids lead to enhanced inhibition of human butyrylcholinesterase”, Natural Product Communications, vol. 9, pp. 455-458, 2014.[Abstract]


Butyrylcholinesterase (BChE) inhibitors were identified from a collection containing cinchonine, cinchonidine and synthetic derivatives, and further characterized using cytotoxicity and molecular docking studies. The most active ones were: (10≡)-10,11-dibromo-10,11-dihydrocinchonidine (11), a competitive inhibitor with Ki = 3.45±0.39 μM, and IC 50 BChE = 9.83±0.30 μM / human (h)BChE = 34.47±4.63 and O-(trimethylsilyl)cinchonine (15), a mixed inhibitor with Kiuc = 1.73±0.46 μM and Kic = 0.85±0.26 μM, and IC 50 BChE = 0.56±0.14 μM / hBChE = 0.24±0.04. In cytotoxicity experiments, ≥80% of the cells remained viable when exposed to concentrations of up to 80 μM of both inhibitors in four different cell lines, including neurons. Due to the bulkier trimethylsilyl side group of 15, it covered the active site of hBChE better than 11 with an OH-group while not being able to fit into the active site gorge of hAChE, thus explaining the selectivity of 15 towards hBChE. More »»

2014

S. Gupta and Dr. Gopi Mohan C., “Dual Binding Site and Selective Acetylcholinesterase Inhibitors Derived from Integrated Pharmacophore Models and Sequential Virtual Screening”, BioMed Research International (Hindawi), 2014.[Abstract]


In this study, we have employed in silico methodology combining double pharmacophore based screening, molecular docking, and ADME/T filtering to identify dual binding site acetylcholinesterase inhibitors that can preferentially inhibit acetylcholinesterase and simultaneously inhibit the butyrylcholinesterase also but in the lesser extent than acetylcholinesterase. 3D-pharmacophore models of AChE and BuChE enzyme inhibitors have been developed from xanthostigmine derivatives through HypoGen and validated using test set, Fischer’s randomization technique. The best acetylcholinesterase and butyrylcholinesterase inhibitors pharmacophore hypotheses Hypo1_A and Hypo1_B, with high correlation coefficient of 0.96 and 0.94, respectively, were used as 3D query for screening the Zinc database. The screened hits were then subjected to the ADME/T and molecular docking study to prioritise the compounds. Finally, 18 compounds were identified as potential leads against AChE enzyme, showing good predicted activities and promising ADME/T properties. More »»

2014

A. Kumar Tewari, Singh, V. Prakash, Yadav, P., Gupta, G., Singh, A., Goel, R. Kumar, Shinde, P., and Dr. Gopi Mohan C., “Synthesis, biological evaluation and molecular modeling study of pyrazole derivatives as selective COX-2 inhibitors and anti-inflammatory agents”, Bioorganic Chemistry, vol. 56, pp. 8 - 15, 2014.[Abstract]


Abstract A novel series of pyrazole derivatives were synthesized and evaluated in vivo for their anti-inflammatory activity in carrageenan-induced rat paw edema model. Among all compounds, 5a, and 5b showed comparable anti-inflammatory activity to Nimesulide, the standard drug taken for the studies. In silico (docking) studies were carried out to investigate the theoretical binding mode of the compounds to target the cyclooxygenase (COX-2) using Autodock 4.2. More »»

2013

A. A1, V, J., P, S., and Dr. Gopi Mohan C., “Uridine monophosphate kinase as potential target for tuberculosis: from target to lead identification”, Interdisciplinary Sciences: Computational Life Sciences (Springer), vol. 5, pp. 296-311, 2013.[Abstract]


Mycobacterium tuberculosis (Mtb) is a causative agent of tuberculosis (TB) disease, which has affected approximately 2 billion people worldwide. Due to the emergence of resistance towards the existing drugs, discovery of new anti-TB drugs is an important global healthcare challenge. To address this problem, there is an urgent need to identify new drug targets in Mtb. In the present study, the subtractive genomics approach has been employed for the identification of new drug targets against TB. Screening the Mtb proteome using the Database of Essential Genes (DEG) and human proteome resulted in the identification of 60 key proteins which have no eukaryotic counterparts. Critical analysis of these proteins using Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways database revealed uridine monophosphate kinase (UMPK) enzyme as a potential drug target for developing novel anti-TB drugs. Homology model of Mtb-UMPK was constructed for the first time on the basis of the crystal structure of E. coli-UMPK, in order to understand its structure-function relationships, and which would in turn facilitate to perform structure-based inhibitor design. Furthermore, the structural similarity search was carried out using physiological inhibitor UTP of Mtb-UMPK to virtually screen ZINC database. Retrieved hits were further screened by implementing several filters like ADME and toxicity followed by molecular docking. Finally, on the basis of the Glide docking score and the mode of binding, 6 putative leads were identified as inhibitors of this enzyme which can potentially emerge as future drugs for the treatment of TB. More »»

2013

S. Sivasundar, Oommen, A. T., Prakash, O., Baskaran, S., Dr. Raja Biswas, Nair, S., Dr. Gopi Mohan C., and Lalitha Biswas, “Molecular defect of 'Prothrombin Amrita': Substitution of arginine by glutamine (Arg553 to Gln) near the Na+ binding loop of prothrombin”, Blood Cells, Molecules, and Diseases, vol. 50, pp. 182-183, 2013.[Abstract]


Prothrombin, the precursor to thrombin, is a serine protease that plays a key role in hemostasis and thrombosis. Several studies have reported mutations resulting from the deletion, substitution, or insertion of a single nucleotide in the prothrombin gene that lead to hypoprothrombinemia, dysprothrombinemia, or thrombosis [1]. One of the most common genetic variations predisposing to deep venous thrombosis is a polymorphism in the factor V gene (Arg506Gln) resulting in the factor V Leiden mutation. Transition of guanine to adenine at nucleotide position 20210 in the 3′ untranslated region of the prothrombin gene is the second most common genetic risk factor for venous thrombosis, which we diagnose in approximately 50 patients annually in Amrita hospital. Several other mutations in the prothrombin gene that are associated with the thrombosis have been reported. The eponym of some of the prothrombin point mutations identified globally are — Padua (Arg271 to His), Corpus Christi (Arg382 to Cys), Obhiro (Arg271 to Cys), Barcelona (Arg273 to Cys), San Antonio (Arg320 to His), Himi (Met337 to Thr and Arg388 to His), Denver (Arg457 to Gln), Dhahran (Arg271 to His), Clamart (Arg320 to Ile), Segovia (Gly319 to Arg), Vellore 1 (Ala362 to Thr), Perijaá (Gly548 to Ala), Himi (Arg388 to His and Met337 to Thr), Habana, Poissy, Houston, Salakta, Thrombin Greenvillae (Arg517 to Gln), etc.

More »»

2012

Aab Pandey, P, Jab, Tripathi, S., and Dr. Gopi Mohan C., “Harnessing human N-type Ca2+ channel receptor by identifying the atomic hotspot regions for its structure-based blocker design”, Molecular Informatics, vol. 31, pp. 643-657, 2012.[Abstract]


<p>The voltage dependent N-type Ca2+ channel (NCC) receptor was identified to have therapeutic potential for the treatment of neuropathic pain and stroke disease. The Ca2+ ion transport through the transmembrane influx is mainly dependent on the closing, opening, or intermediate state gating mechanism of NCC. Harnessing this dynamic gating mechanism at the structural level is an important and challenging physiological phenomenon. The three dimensional (3D) structure of this membrane receptor is not yet experimentally determined to understand its mechanism of action. Based on these observations, we have developed for the first time the structure of the closed state of the NCC receptor at the pore forming domains which mainly involve three transmembrane helices (TMhs) S5, P and S6. Hot-spot binding site residues of this receptor model were identified by molecular docking technique using amlodipine, cilnidipine and nifedipine compounds known to be potent Ca 2+ channel antagonists. Further, the Ca2+ ion permeability and the hydrophobic gating mechanism provided better structural and functional insights on the NCC receptor. These results are in consonance with other Ca 2+ channel receptors and would provide guidance for further biochemical investigations. Copyright © 2012 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim.</p>

More »»

2012

Da Karlsson, Fallarero, Aa, Brunhofer, Gab, Mayer, Cb, Prakash, Oc, Dr. Gopi Mohan C., Vuorela, Pa, and Erker, Tb, “The exploration of thienothiazines as selective butyrylcholinesterase inhibitors”, European Journal of Pharmaceutical Sciences, vol. 47, pp. 190-205, 2012.[Abstract]


The role of butyrylcholinesterase (BChE) in the progression of Alzheimer's disease (AD) has recently become more crucial. In the AD brain, selective BChE inhibitors have been demonstrated to have a beneficial effect in vivo, probably by recovering cholinergic activity and/or by restoring AChE:BChE activity ratios to the levels observed in the healthy brain. Thienothiazines are compounds sharing some structural features with phenothiazines, which are known to be potent BChE inhibitors. Thus, in this contribution 45 thienothiazines were investigated for their BChE inhibitory activity. Six of them were proven to be potent and selective inhibitors of equine BChE's hydrolase activity. Structure-activity relationships were laid out, and a tentative pharmacophore model for BChE inhibitors of the thienothiazine type was proposed. The most active compound, 3f, displayed a mixed type of inhibition and was also active against the human BChE (huBChE) with an IC50 huBChE of 0.51 ± 0.07 μM. Computational studies suggested that 3f likely binds to the catalytic site and nearby to the peripheral site of the huBChE in an extended form. In addition, the chemical space occupied by the active thienothiazines, as opposed to phenothiazines and other representative chemical classes of BChE inhibitors, was explored with the aid of ChemGPS-NP, and the relevant chemical space regions were identified. This study shows for the first time that thienothiazines represent a new group of BChE inhibitors that can be used as molecular probes for studying the role of BChE in the brain or for developing newer drug leads for AD therapy. © 2012 Elsevier B.V. All rights reserved.

More »»

2012

Aad Arvind, Kumar, Va, Saravanan, Pb, and Dr. Gopi Mohan C., “Homology modeling, molecular dynamics and inhibitor binding study on MurD ligase of Mycobacterium tuberculosis”, Interdisciplinary Sciences: Computational Life Sciences, vol. 4, pp. 223-238, 2012.[Abstract]


The cell wall of mycobacterium offers well validated targets which can be exploited for discovery of new lead compounds. MurC-MurF ligases catalyze a series of irreversible steps in the biosynthesis of peptidoglycan precursor, i.e. MurD catalyzes the ligation of D-glutamate to the nucleotide precursor UMA. The three dimensional structure of Mtb-MurD is not known and was predicted by us for the first time using comparative homology modeling technique. The accuracy and stability of the predicted Mtb-MurD structure was validated using Procheck and molecular dynamics simulation. Key interactions in Mtb-MurD were studied using docking analysis of available transition state inhibitors of E.coli-MurD. The docking analysis revealed that analogues of both L and D forms of glutamic acid have similar interaction profiles with Mtb-MurD. Further, residues His192, Arg382, Ser463, and Tyr470 are proposed to be important for inhibitor-(Mtb-MurD) interactions. We also identified few pharmacophoric features essential for Mtb-MurD ligase inhibitory activity and which can further been utilized for the discovery of putative antitubercular chemotherapy. © 2012 International Association of Scientists in the Interdisciplinary Areas and Springer-Verlag Berlin Heidelberg.

More »»

2012

G. Brunhofer, Fallarero, A., Karlsson, D., Batista-Gonzalez, A., Shinde, P., Dr. Gopi Mohan C., and Vuorela, P., “Exploration of Natural Compounds as Sources of New Bifunctional Scaffolds Targeting Cholinesterases and Beta Amyloid Aggregation: The Case of Chelerythrine”, Bioorganic and Medicinal Chemistry, vol. 20, pp. 6669-6679, 2012.[Abstract]


The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin - chelerythrine - acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs. © 2012 Elsevier Ltd. All rights reserved.

More »»

2011

S. Gupta and Dr. Gopi Mohan C., “3D-pharmacophore Model Based Virtual Screening to Identify Dual-binding Site and Selective Acetylcholinesterase Inhibitors”, Medicinal Chemistry Research, vol. 20, pp. 1422–1430, 2011.[Abstract]


The formation of $\beta$-amyloid plaques in the brain is a key neurodegenerative event in Alzheimer's disease (AD). Interestingly, research on acetylcholinesterase (AChE) enzyme has increased due to findings supporting this enzyme involvement in the $\beta$-amyloid peptide fibril formation during AD pathogenesis. In this investigation, chemical features based 3D pharmacophore models were developed from structurally diverse xanthostigmine derivatives, known inhibitors of AChE enzyme, using 3D-QSAR pharmacophore generation module in Discovery Studio2.5 (DS2.5). The constructed pharmacophore models for AChE inhibitors was further cross-validated using test set and Cat-Scramble methodology. The best quantitative pharmacophore model Hypo1, was used for screening the chemical databases of small compounds including Specs, NCI, and IBScreen, to identify the new compounds that are presumably able to act as dual-binding site AChE inhibitors. The screened virtual hits were then subjected to the Lipinski's rule of five, blood–brain barrier (BBB), PSA, LogS, percent human oral absorption, and toxicity analysis. Finally, 32 compounds were identified as potential leads against AChE enzyme, showing good estimated activities and promising ADMET properties. Molecular docking of these compounds using FlexX software showed catalytic and peripheral anionic binding site interactions, so called dual binding of the AChE enzyme. Docking study was also performed on butyrylcholinesterase in order to understand the compound selectivity. This study may assist in the discovery and design of novel dual binding site and selective AChE inhibitors with potent inhibitory activity.

More »»

2011

Dr. Gopi Mohan C., “Impact of Computational Structure-Based Predictive Toxicology in Drug Discovery”, Combinatorial Chemistry & High Throughput Screening, vol. 14, pp. 417-426, 2011.[Abstract]


Computational tools for predicting toxicity have been envisioned to have the potential to broadly impact up on the attrition rate of compounds in pre-clinical drug discovery and development. An integrated approach of computerassisted, predictive, and physico-chemical properties of a compound, along with its in vitro and in vivo analysis, needs to be routinely exercised in the lead identification and lead optimization processes. Starting with a good lead can save a lot of money and it can significantly reduce the entire drug discovery process. The journey towards triple R's- reduce, replace and refine, further proves to be successful in predicting adverse drug reactions in patients (or animals) enrolled in clinical trials. However, the impact of predictive toxicity analysis was modest and relatively narrow in scope, due to the limited domain knowledge in this field. It is important to note that advances within medical science and newer approaches in drug development will require predictive toxicology applications to be viable. The field of computational toxicology has been heading in a direction more relevant to human diseases by reducing the adverse drug reactions. Therefore, efforts must be directed to integrating these tools relevant to the goal of preventing undesired toxicity in pre-clinical trials followed by different phases of clinical trials.

More »»

2011

V. Kumar, Saravanan, P., Arvind, A., and Dr. Gopi Mohan C., “Identification of Hotspot Regions of MurB Oxidoreductase Enzyme using Homology Modeling, molecular Dynamics and Molecular Docking Techniques”, Journal of Molecular Modeling, vol. 17, pp. 939–953, 2011.[Abstract]


Despite the availability of effective chemotherapy and a moderately protective vaccine, new anti-tuberculosis agents are urgently needed to decrease the global incidence of tuberculosis (TB) disease. The MurB gene belongs to the bacterial cell wall biosynthesis pathway and is an essential drug target in Mycobacterium tuberculosis (Mtb) that has no mammalian counterparts. Here, we present an integrated approach involving homology modeling, molecular dynamics and molecular docking studies on Mtb-MurB oxidoreductase enzyme. A homology model of Mtb-MurB enzyme was built for the first time in order to carry out structure-based inhibitor design. The accuracy of the model was validated using different techniques. The molecular docking study on this enzyme was undertaken using different classes of well known MurB inhibitors. Estimation of binding free energy by docking analysis indicated the importance of Tyr155, Arg156, Ser237, Asn241 and His304 residues within the Mtb-MurB binding pocket. Our computational analysis is in good agreement with experimental results of site-directed mutagenesis. The present study should therefore play a guiding role in the experimental design of Mtb-MurB inhibitors for in vitro/in vivo analysis.

More »»

2011

R. B. Birari, Gupta, S., Dr. Gopi Mohan C., and Bhutani, K. K., “Antiobesity and Lipid Lowering Effects of Glycyrrhiza Chalcones: Experimental and Computational Studies”, Phytomedicine, vol. 18, pp. 795 - 801, 2011.[Abstract]


Twelve flavonoids (1–12), isolated from Glycyrrhiza glabra roots were evaluated for their pancreatic lipase (PL) inhibitory activity in vitro. The structures of the isolated compounds were elucidated by spectroscopic methods. Amongst all the compounds 7, 8, 10 and 11 showed strong inhibition against PL with IC50 values of 7.3μM, 35.5μM, 14.9μM and 37.6μM, respectively. Molecular docking studies on the most active compound 7 revealed that it binds with the key amino acid residues of the PL active site. In silico absorption, distribution, metabolism and excretion (ADME) parameters were also computed on the active compounds to determine their preliminary pharmacokinetic properties. Further, investigations were carried out to determine the antiobesity and lipid lowering effects of 7 and 10 in high fat diet (HFD) fed male SD rats. In the rats supplemented with compound 7 the body weight increase was only 23.2±3.6g as compared to 64.2±0.5g in the HFD control group while in the rats treated with compound 10 showed 23.2±3.6g weight gain only. Compound 7 decreased the levels of plasma total cholesterol (TC) to 84.6±1.4mg/dl and plasma total triglycerides (TG) to 128.8±6.0mg/dl. Compound 10 also lowered the plasma TC and TG levels considerably. The results indicate the potential of the chalcone scaffold as a source of PL inhibitors for preventing obesity.

More »»

2011

R. Gautam, Jachak, S. M., Kumar, V., and Dr. Gopi Mohan C., “Synthesis, Biological Evaluation and Molecular Docking Studies of Stellatin Derivatives as Cyclooxygenase (COX-1, COX-2) Inhibitors and Anti-inflammatory Agents”, Bioorganic & Medicinal Chemistry Letters, vol. 21, pp. 1612 - 1616, 2011.[Abstract]


Stellatin (4), isolated from Dysophylla stellata is a cyclooxygenase (COX) inhibitor. The present study reports the synthesis and biological evaluation of new stellatin derivatives for COX-1, COX-2 inhibitory and anti-inflammatory activities. Eight derivatives showed more pronounced COX-2 inhibition than stellatin and, 17 and 21 exhibited the highest COX-2 inhibition. They also exhibited the significant anti-inflammatory activity in TPA-induced mouse ear edema assay and their anti-inflammatory effects were more than that of stellatin and indomethacin at 0.5mg/ear. The derivatives were further evaluated for antioxidant activity wherein 16 and 17 showed potent free radical scavenging activity against DPPH and ABTS radicals. Molecular docking study revealed the binding orientations of stellatin and its derivatives into the active sites of COX-1 and COX-2 and thereby helps to design the potent inhibitors.

More »»

2011

V. Jain, Saravanan, P., Arvind, A., and Dr. Gopi Mohan C., “First Pharmacophore Model of CCR3 Receptor Antagonists and its Homology Model-Assisted, Stepwise Virtual Screening”, Chemical Biology & Drug Design, vol. 77, pp. 373-387, 2011.[Abstract]


CCR3, a G protein-coupled receptor, plays a central role in allergic inflammation and is an important drug target for inflammatory diseases. To understand the structure–function relationship of CCR3 receptor, different computational techniques were employed, which mainly include: (i) homology modeling of CCR3 receptor, (ii) 3D-quantitative pharmacophore model of CCR3 antagonists, (iii) virtual screening of small compound databases, and (iv) finally, molecular docking at the binding site of the CCR3 receptor homology model. Pharmacophore model was developed for the first time, on a training data set of 22 CCR3 antagonists, using catalystHypoRefine program. Best hypothesis (Hypo1) has three different chemical features: two hydrogen-bond acceptors, one hydrophobic, and one ring aromatic. Hypo1 model was further validated using (i) 87 test set CCR3 antagonists, (ii) Cat Scramble randomization technique, and (iii) Decoy data set. Molecular docking studies were performed on modeled CCR3 receptor using 303 virtually screened hits, obtained from small compound database virtual screening. Finally, five hits were identified as potential leads against CCR3 receptor, which exhibited good estimated activities, favorable binding interactions, and high docking scores. These studies provided useful information on the structurally vital residues of CCR3 receptor involved in the antagonist binding, and their unexplored potential for the future development of potent CCR3 receptor antagonists.

More »»

2011

S. Gupta, Fallarero, A., Järvinen, P., Karlsson, D., Johnson, M. S., Vuorela, P. M., and Dr. Gopi Mohan C., “Discovery of Dual Binding Site Acetylcholinesterase Inhibitors Identified by Pharmacophore Modeling and Sequential Virtual Screening Techniques”, Bioorganic & Medicinal Chemistry Letters, vol. 21, pp. 1105 - 1112, 2011.[Abstract]


Dual binding site acetylcholinesterase (AChE) inhibitors are promising for the treatment of Alzheimer’s disease (AD). They alleviate the cognitive deficits and AD-modifying agents, by inhibiting the β-amyloid (Aβ) peptide aggregation, through binding to both the catalytic and peripheral anionic sites, the so called dual binding site of the AChE enzyme. In this Letter, chemical features based 3D-pharmacophore models were developed based on the eight potent and structurally diverse AChE inhibitors (I–VIII) obtained from high-throughput in vitro screening technique. The best 3D-pharmacophore model, Hypo1, consists of two hydrogen-bond acceptor lipid, one hydrophobe, and two hydrophobic aliphatic features obtained by Catalyst/HIPHOP algorithm adopted in Discovery studio program. Hypo1 was used as a 3D query in sequential virtual screening study to filter three small compound databases. Further, a total of nine compounds were selected and followed on in vitro analysis. Finally, we identified two leads—Specs1 (IC50=3.279μM) and Spec2 (IC50=5.986μM) dual binding site compounds from Specs database, having good AChE enzyme inhibitory activity.

More »»

2011

S. Gupta, Fallarero, A., Vainio, M. J., Saravanan, P., J. Puranen, S., Järvinen, P., Johnson, M. S., Vuorela, P. M., and Dr. Gopi Mohan C., “Molecular Docking Guided Comparative GFA, G/PLS, SVM and ANN Models of Structurally Diverse Dual Binding Site Acetylcholinesterase Inhibitors”, Molecular Informatics, vol. 30, pp. 689-706, 2011.[Abstract]


Recently discovered 42 AChE inhibitors binding at the catalytic and peripheral anionic site were identified on the basis of molecular docking approach, and its comparative quantitative structure–activity relationship (QSAR) models were developed. These structurally diverse inhibitors were obtained by our previously reported high-throughput in vitro screening technique using 384-well plate’s assay based on colorimetric method of Ellman. QSAR models were developed using (i) genetic function algorithm, (ii) genetic partial least squares, (iii) support vector machine and (iv) artificial neural network techniques. The QSAR model robustness and significance was critically assessed using different cross-validation techniques on test data set. The generated QSAR models using thermodynamic, electrotopological and electronic descriptors showed that nonlinear methods are more robust than linear methods, and provide insight into the structural features of compounds that are important for AChE inhibition

More »»

2010

A. Pandey, Mungalpara, J., and Dr. Gopi Mohan C., “Comparative molecular field analysis and comparative molecular similarity indices analysis of hydroxyethylamine derivatives as selective human BACE-1 inhibitor”, Molecular Diversity, vol. 14, pp. 39–49, 2010.[Abstract]


Three-dimensional quantitative structure–activity relationship (3D-QSAR) models were developed based on comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), on a series of 43 hydroxyethylamine derivatives, acting as potent inhibitors of $\beta$-site amyloid precursor protein (APP) cleavage enzyme (BACE-1). The crystal structure of the BACE-1 enzyme (PDB ID: 2HM1) with one of the most active compound 28 was available, and we assumed it to be the bioactive conformation of the studied series, for 3D-QSAR analysis. Statistically significant 3D-QSAR model was established on a training set of 34 compounds, which were validated by a test set of 9 compounds. For the best CoMFA model, the statistics are, r 2 =&nbsp; 0.998, {\$}{\$}{\{}r^{\{}2{\}}{\_}{\{}{\backslash}rm cv{\}} = 0.810{\}}{\$}{\$

More »»

2010

M. Awale, Kumar, V., Saravanan, P., and Dr. Gopi Mohan C., “Homology modeling and atomic level binding study of Leishmania MAPK with inhibitors”, Journal of Molecular Modeling, vol. 16, pp. 475–488, 2010.[Abstract]


The current therapy for leishmaniasis is not sufficient and it has two severe drawbacks, host-toxicity and drug resistance. The substantial knowledge of parasite biology is not yet translating into novel drugs for leishmaniasis. Based on this observation, a 3D structural model of Leishmania mitogen-activated protein kinase (MAPK) homologue has been developed, for the first time, by homology modeling and molecular dynamics simulation techniques. The model provided clear insight in its structure features, i.e. ATP binding pocket, phosphorylation lip, and common docking site. Sequence-structure homology recognition identified Leishmania CRK3 (LCRK3) as a distant member of the MAPK superfamily. Multiple sequence alignment and 3D structure model provided the putative ATP binding pocket of Leishmania with respect to human ERK2 and LCRK3. This analysis was helpful in identifying the binding sites and molecular function of the Leishmania specific MAPK homologue. Molecular docking study was performed on this 3D structural model, using different classes of competitive ATP inhibitors of LCRK3, to check whether they exhibit affinity and could be identified as Leishmania MAPK specific inhibitors. It is well known that MAP kinases are extracellular signal regulated kinases ERK1 and ERK2, which are components of the Ras-MAPK signal transduction pathway which is complexed with HDAC4 protein, and their inhibition is of significant therapeutic interest in cancer biology. In order to understand the mechanism of action, docking of indirubin class of molecules to the active site of histone deacetylase 4 (HDAC4) protein is performed, and the binding affinity of the protein-ligand interaction was computed. The new structural insights obtained from this study are all consistent with the available experimental data, suggesting that the homology model of the Leishmania MAPK and its ligand interaction modes are reasonable. Further the comparative molecular electrostatic potential and cavity depth analysis of Leishmania MAPK and human ERK2 suggested several important differences in its ATP binding pocket. Such differences could be exploited in the future for designing Leishmania specific MAPK inhibitors.

More »»

2010

J. Mungalpara, Pandey, A., Jain, V., and Dr. Gopi Mohan C., “Molecular modelling and QSAR analysis of some structurally diverse N-type calcium channel blockers”, Journal of Molecular Modeling, vol. 16, pp. 629–644, 2010.[Abstract]


A quantitative structure–activity relationship (QSAR) analysis was performed on a data set of 104 molecules showing N-type calcium channel blocking activity. Several types of descriptors, including electrotopological, structural, thermodynamics and ADMET, were used to derive a quantitative relationship between N-type calcium channel blocking activity and structural properties. The genetic algorithm-based genetic function approximation (GFA) method of variable selection was used to generate the 2D-QSAR model. The model was established on a training set of 83 molecules, and validated by a test set of 21 molecules. The model was developed using five information-rich descriptors–-Atype{\_}C{\_}24, Atype{\_}N{\_}68, Rotlbonds, S{\_}sssN, and ADME{\_}Solubility–-playing an important role in determining N-type calcium channel blocking activity. For the best QSAR model (model 4), the statistics were r 2þinspace}=þinspace}0.798; q 2þinspace}=þinspace}0.769; nþinspace}=þinspace}83 for the training set. This model was further validated using the leave-one-out (LOO) cross-validation approach, Fischer statistics (F), Y-randomisation test, and predictions based on the test data set. The resulting descriptors produced by QSAR model 4 were used to identify physico-chemical features relevant to N-type calcium channel blocking activity.

More »»

2010

V. Jain, Pandey, A., Gupta, S., and Dr. Gopi Mohan C., “Ligand-based molecular design of 4-benzylpiperidinealkylureas and amides as CCR3 antagonists”, Journal of Molecular Modeling, vol. 16, pp. 669–676, 2010.[Abstract]


Asthma is an inflammatory disease of the lungs. Clinical studies suggest that eotaxin and chemokine receptor-3 (CCR3) play a primary role in the recruitment of eosinophils in allergic asthma. Development of novel and potent CCR3 antagonists could provide a novel mechanism for inhibition of this recruitment process, thereby preventing asthma. With the intention of designing new ligands with enhanced inhibitor potencies against CCR3, a 3D-QSAR CoMFA study was carried out on 41 4-benzylpiperidinealkylureas and amide derivatives. The best statistics of the developed CoMFA model were r 2þinspace}=þinspace}0.960, {\$}{\$} r{\_}{\{}cv{\}}^2 = 0.589 {\$}{\$} , nþinspace}=þinspace}32 for the training set and {\$}{\$} r{\_}{\{}pred{\}}^2 = 0.619 {\$}{\$} , nþinspace}=þinspace}9 for the test set. The generated 3D-QSAR contribution maps shed some light on the effects of the substitution pattern related to CCR3 antagonist activity.

More »»

2010

A. Kumar Tewari, Srivastava, P., Singh, V. Prakash, Singh, A., Goel, R. Kumar, and Dr. Gopi Mohan C., “Novel Anti-inflammatory Agents Based on Pyrazole Based Dimeric Compounds; Design, Synthesis, Docking and in Vivo Activity”, Chemical and Pharmaceutical Bulletin, vol. 58, pp. 634-638, 2010.

2010

P. P. Jarvinen, Fallarero, A., Gupta, S., Dr. Gopi Mohan C., Hatakka, A. I., and Vuorela, P. M., “Miniaturization and Validation of the Ellman's Reaction Based Acetylcholinesterase Inhibitory Assay into 384-Well Plate Format and Screening of a Chemical Library”, Combinatorial Chemistry & High Throughput Screening, vol. 13, pp. 278-284, 2010.[Abstract]


The aim of this study was to screen for acetylcholinesterase (AChE) inhibitors from a large chemical library of commercially available compounds. For this purpose, the Ellman's reaction based assay was miniaturized into 384-well plate format, and two modifications of the kinetic protocol were studied with the aim of developing a rapid screening platform that could ensure high efficiency in finding true hits. It was proven that when starting the kinetic reaction by addition of the substrate, better assay performance was achieved and more practical benefits obtained. Using the optimized automated protocol, a chemical library of 56,320 compounds was screened. A total of 350 positive hits were identified and their IC50 calculated. Three highly active compounds were identified with IC50 values close or even lower to physostigmine (&lt; 0.1 M). The activity towards butyrylcholinesterase (BChE) of these three most active hits was also evaluated. The most active hit (IC50(AChE) = 0.019 M), was identified as a new inhibitor, belonging to ChemDiv chemical library: (N-[3-(3,5-dimethyl-1-piperidinyl)propyl]-5-ethyl-2-methyl-8-oxo-thieno[2',3':4,5]pyrrolo[1,2-d] [1,2,4] triazine- 7(8H)-acetamid), with no other biological activities reported until now. The interactions of this hit with both cholinesterases were further analyzed using computational docking studies. To our knowledge, this is the largest published screening campaign of commercially available compounds that has focused on finding new AChE inhibitors. The miniaturized 384-well plate format of the Ellman's method was proven to be robust and to perform reliably.

More »»

2010

Dr. Gopi Mohan C., SK, A., AK, S., and D, G., “Biological Evaluation and Molecular Docking of Aryl Hydrazines and Hydrazides for Anticancer Activity”, Indian Journal of Experimental Biology, vol. 48, pp. 265-268, 2010.[Abstract]


Aryl hydrazine and hydrazide analogues were synthesized based on p-tolyl hydrazine, isolated as a breakdown product of a secondary metabolite from the mushroom, Agaricus bisporus, and tested to be highly active molecule than 5-fluorouracil in in vitro anticancer studies. The synthesized analogues were tested for anticancer activity using NCI protocol. Anolgues 12 and 15 emerged as molecules with significant in vitro anticancer activity. Molecular docking study revealed the binding orientations of aryl hydrazines and hydrazides analogues in the active sites of thymidylate synthase.

More »»

2010

P. Saravanan, Venkatesan, S. K., Dr. Gopi Mohan C., Patra, S., and Dubey, V. Kumar, “Mitogen Activated Protein Kinase 4 of Leishmania Parasite as a Therapeutic Target”, European Journal of Medicinal Chemistry, vol. 45, pp. 5662 - 5670, 2010.[Abstract]


Protein kinases are important regulators of many different cellular processes such as transcriptional control, cell cycle progression and differentiation, and have drawn much attention as potential drug targets. Leishmania mexicana mitogen-activated protein kinase 4 (LmxMPK4) is crucial for the survival of the parasite. As the crystal structure of the enzyme is not known, we have used bioinformatics techniques to model LmxMPK4 structure. The current study reveals conservation of all sequence and structural motifs of LmxMPK4. Study shows mitogen-activated protein kinases are highly conserved throughout different Leishmania species and significant divergence is observed towards mammalian mitogen-activated protein kinases. Additionally, using virtual docking methods, we have identified inhibitors for LmxMPK4. The sequence and structure analysis results were helpful in identifying the ligand binding sites and molecular function of the Leishmania specific mitogen-activated protein kinase

More »»

2008

Dr. Gopi Mohan C. and Gandhi, T., “Therapeutic Potential of Voltage Gated Calcium Channels”, Mini Reviews in Medicinal Chemistry, vol. 8, pp. 1285-1290, 2008.[Abstract]


Voltage-gated Calcium channels (VGCCs) play important roles in neurotransmitter release, excitationcontraction coupling, hormone secretion, and a variety of other physiological processes. Currently, there exist ion channel therapeutics for anxiety, epilepsy, hypertension, insomnia and pain. There is limited amount of study in this area despite their relevance to human disease and VGCCs remain considerably underexploited. The present review mainly focuses on calcium channel blockers (CCBs), especially for L-type channels and T-type channels, and therein lie some of the opportunities and advantages associated with VGCCs as drug targets.

More »»

2008

D. Garg, Gandhi, T., and Dr. Gopi Mohan C., “Exploring QSTR and toxicophore of hERG K+ channel blockers using GFA and HypoGen techniques”, Journal of Molecular Graphics and Modelling, vol. 26, pp. 966 - 976, 2008.[Abstract]


Predictive quantitative structure–toxicity and toxicophore models were developed for a diverse series of hERG K+ channel blockers, acting as anti-arrhythmic agents using QSAR+ module in Cerius2 and HypoGen module in Catalyst software, respectively. The 2D-QSTR analysis has been performed on a dataset of 68 molecules carefully selected from literature for which IC50 values measured on hERG K+ channels expressed in mammalian cells lines using the voltage patch clamp assay technique were reported. Their biological data, expressed as IC50, spanned from 7.0nM to 1.4mM, with 7 orders difference. Several types of descriptors including electrotopological, thermodynamic, ADMET, graph theoretical (topological and information content) were used to derive a quantitative relationship between the channel blockers and its physico-chemical properties. Statistically significant QSTR model was obtained using genetic function approximation methodology, having seven descriptors, with a correlation coefficient (r2) of 0.837, cross-validated correlation coefficient (q2) of 0.776 and predictive correlation coefficient (rpred2) of 0.701, indicating the robustness of the model. Toxicophore model generated using HypoGen module in Catalyst, on these datasets, showed three important features for hERG K+ channel blockers, (i) hydrophobic group (HP), (ii) ring aromatic group (RA) and (iii) hydrogen bond acceptor lipid group (HBAl). The most predictive hypothesis (Hypo 1), consisting of these three features had a best correlation coefficient of 0.820, a low rms deviation of 1.740, and a high cost difference of 113.50, which represents a true correlation and a good predictivity. The hypothesis, Hypo 1 was validated by a test set consisting of 12 molecules and by a cross-validation of 95% confidence level. Accordingly, our 2D-QSTR and toxicophore model has strong predictivity to identify structurally diverse hERG K+ channel blockers with desired biological activity. These models provide a useful framework for understanding binding, and gave structural insight into the specific protein–ligand interactions responsible for affinity, and how one might modify any given structure to mitigate binding.

More »»

2008

M. Awale and Dr. Gopi Mohan C., “3D-QSAR CoMFA Analysis of C5 Substituted Pyrrolotriazines as HER2 (ErbB2) Inhibitors”, Journal of Molecular Graphics and Modelling, vol. 26, pp. 1169 - 1178, 2008.[Abstract]


Human cancers are characterized by an up-regulation of some of the RTKs (EGFR and HER2) and have been clinically validated as targets for cancer therapy. C4 and C5 substituted pyrrolotriazines showed dual inhibition of HER2 and EGFR protein tyrosine kinases. To explore the relationship between the structures of the aforementioned classes of molecules and their HER2 inhibition, 3D-QSAR CoMFA analysis have been performed. The developed CoMFA model showed statistically significant results with good predictive ability.

More »»

2008

M. Awale and Dr. Gopi Mohan C., “Molecular Docking Guided 3D-QSAR CoMFA Analysis of N-4-Pyrimidinyl-1H-indazol-4-amine Inhibitors of leukocyte-specific Protein Tyrosine Kinase”, Journal of Molecular Modeling, vol. 14, pp. 937–947, 2008.[Abstract]


Inhibition of leukocyte-specific protein tyrosine kinase (Lck) activity offers one of the approaches for the treatment of T-cell mediated inflammatory disorders including rheumatoid arthritis, transplant rejection and inflammatory bowel disease. To explore the relationship between the structures of the N-4 Pyrimidinyl-1H-indazol-4-amines and their Lck inhibition, 3D-QSAR study using CoMFA analysis have been performed on a dataset of 42 molecules. The bioactive conformation of the template molecule, selected as the most potent molecule 23 from the series was obtained by performing molecular docking at the ATP binding site of Lck, which is then used to build the rest of the molecules in the series. The constructed CoMFA model is robust with {\$}{\$}r{\_}{\{}cv{\}}^2 {\$}{\$} of 0.603 and conventional r2 of 0.983. The predictive power of the developed model was obtained using a test set of 10 molecules, giving predictive correlation coefficient of 0.921. CoMFA contour analysis was performed to obtain useful information about the structural requirements for the Lck inhibitors which could be utilized in its future design.

More »»

2008

A. Fallarero, Oinonen, P., Gupta, S., Blom, P., Galkin, A., Dr. Gopi Mohan C., and Vuorela, P. M., “Inhibition of Acetylcholinesterase by Coumarins: The Case of Coumarin 106”, Pharmacological Research, vol. 58, pp. 215 - 221, 2008.[Abstract]


In this contribution, from a coumarin library consisting of 29 compounds including natural and synthetic derivatives, an active acetylcholinesterase (AChE) inhibitor (coumarin 106) was found. This circumstance leaded us to continue with the pharmacological characterization of coumarin 106. The first study with the coumarin library was performed using a 96-microtiter well plate assay based on Ellman's reaction. Coumarins were assayed at 5 and 30μM, and coumarin 106 was found the most active inhibitor at both concentrations. The follow-up analysis using kinetic studies demonstrated that coumarin 106 displays mixed-type AChE inhibition with a pIC50=4.97±0.09 and Ki=2.36±0.17μM. The ability of this molecule to interact with AChE was further confirmed through computational studies, in which a primary binding was proved to occur at the active gorge site, while a secondary binding was demonstrated at the peripheral anionic site. Also, coumarin 106 was shown to inhibit butyrylcholinesterase (BChE) with slightly lower potency (pIC50=4.56±0.06), and found to be non-toxic in Caco-2 cells. The combination of these findings makes coumarin 106 an attractive molecule for further investigation. This is the first report where AChE inhibitory activity has been associated with coumarin 106, and proof has been given of its convenience as a lead molecule.

More »»

Publication Type: Patent

Year of Publication Title

2018

Dr. Gopi Mohan C., Raja Biswas, V. Kumar, A., and CP, A., “Composition and Method of Treatment of Bacterial Infections”, 2018.[Abstract]


The invention is intended for a treatment of severe infections using an injectable drug-delivery system comprising nanoparticles of a biodegradable polymer with incorporated antibacterial drug.

More »»

2018

Dr. Gopi Mohan C., Menon, K. N., and Jose, J., “A Composition and a Method for Treatment of Diseases Associated with Central Nervous System Inflammation”, 2018.