Dr. Prashanth Athri currently serves as Associate Professor at the Department of Computer Science, School of Engineering, Bengaluru. He has worked at Strand Life Sciences, Bengaluru as a Senior Specialist (bioinformatics data analytics), and has held post-doctoral fellowships EPF Lausanne, Switzerland & Emory University, Atlanta, USA. He received his Ph. D. in Computational Chemistry and Bioinformatics (minor) at Georgia State University, preceded by M. S. in Computer Science and Bioinformatics (minor). His research interests include big data analytics of bioinformatics data towards application in the personalized medicine space. He conducts research into the application of semantic web technologies, database integration and parallalized searches to enable data centered knowledge mining in this field. He also develops evolution inspired algorithms to build hypotheses in the area of new generation drug discovery. Additionally, Dr. Prashanth explores the application of high performance.


  • Bioinformatics


Publication Type: Journal Article
Year of Publication Publication Type Title
2012 Journal Article M. Doemer, Guglielmi, M., Prashanth, A., Nagornova, N. S., Rizzo, T. R., Boyarkin, O. V., Tavernelli, I., and Rothlisberger, U., “Assessing the performance of computational methods for the prediction of the ground state structure of a cyclic decapeptide”, International Journal of Quantum Chemistry, vol. 113, pp. 808–814, 2012.[Abstract]

We benchmark the performance of various computational approaches, ranging from the classical nonpolarizable force fields AMBER FF96 and FF99SB, the polarizable force fields AMBER FF02polEP and AMOEBAbio09 to the semiempirical DFT method SCC-DFTB. The test set consists of nine conformations of gas-phase protonated gramicidin S, a cyclic decapeptide. We discuss their structural features in relation to the intrinsic lowest energy structure, which has been solved recently by a combination of cold ion spectroscopy and high level theoretical methods (Nagornova et al., Angew Chem Int Ed 2011, 50, 5383). As a reference, we use the energetics at the M05-2X level of theory. The latter has been validated as a suitable reference method in predicting the correct ground state structure of gas-phase protonated bare and microsolvated tryptophan as well as gas-phase protonated gramicidin S by comparison to experiment. We discuss the performance of the different more approximate methods in relation to their potential use as efficient and reliable tools to explore conformational space for the generation of candidate structures before refinement at the DFT level.

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2011 Journal Article D. Enderle, Beisel, C., Stadler, M. B., Gerstung, M., Prashanth, A., and Paro, R., “Polycomb preferentially targets stalled promoters of coding and non-coding transcripts”, Genome Research, vol. 21, pp. 216–226, 2011.[Abstract]

The Polycomb group (PcG) and Trithorax group (TrxG) of proteins are required for stable and heritable maintenance of repressed and active gene expression states. Their antagonistic function on gene control, repression for PcG and activity for TrxG, is mediated by binding to chromatin and subsequent epigenetic modification of target loci. Despite our broad knowledge about composition and enzymatic activities of the protein complexes involved, our understanding still lacks important mechanistic detail and a comprehensive view on target genes. In this study we use an extensive data set of ChIP-seq, RNA-seq, and genome-wide detection of transcription start sites (TSSs) to identify and analyze thousands of binding sites for the PcG proteins and Trithorax from a Drosophila S2 cell line. In addition of finding a preference for stalled promoter regions of annotated genes, we uncover many intergenic PcG binding sites coinciding with nonannotated TSSs. Interestingly, this set includes previously unknown promoters for primary transcripts of microRNA genes, thereby expanding the scope of Polycomb control to noncoding RNAs essential for development, apoptosis, and growth.

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2011 Journal Article E. Brunk, Ashari, N., Prashanth, A., Campomanes, P., F. de Carvalho, F., Curchod, B. F. E., Diamantis, P., Doemer, M., Garrec, J., Laktionov, A., Micciarelli, M., Neri, M., Palermo, G., Penfold, T. J., Vanni, S., Tavernelli, I., and Rothlisberger, U., “Pushing the Frontiers of First-Principles Based Computer Simulations of Chemical and Biological Systems”, Chimia, vol. 65, pp. 667–671, 2011.[Abstract]

The Laboratory of Computational Chemistry and Biochemistry is active in the development and application of first-principles based simulations of complex chemical and biochemical phenomena. Here, we review some of our recent efforts in extending these methods to larger systems, longer time scales and increased accuracies. Their versatility is illustrated with a diverse range of applications, ranging from the determination of the gas phase structure of the cyclic decapeptide gramicidin S, to the study of G protein coupled receptors, the interaction of transition metal based anti-cancer agents with protein targets, the mechanism of action of DNA repair enzymes, the role of metal ions in neurodegenerative diseases and the computational design of dye-sensitized solar cells. Many of these projects are done in collaboration with experimental groups from the Institute of Chemical Sciences and Engineering (ISIC) at the EPFL.

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2010 Journal Article A. Carl Shetty, Prashanth, A., Mondal, K., Horner, V. L., Steinberg, K. Meltz, Patel, V., Caspary, T., Cutler, D. J., and Zwick, M. E., “SeqAnt: A web service to rapidly identify and annotate DNA sequence variations”, BMC Bioinformatics, vol. 11, 2010.[Abstract]

The enormous throughput and low cost of second-generation sequencing platforms now allow research and clinical geneticists to routinely perform single experiments that identify tens of thousands to millions of variant sites. Existing methods to annotate variant sites using information from publicly available databases via web browsers are too slow to be useful for the large sequencing datasets being routinely generated by geneticists. Because sequence annotation of variant sites is required before functional characterization can proceed, the lack of a high-throughput pipeline to efficiently annotate variant sites can act as a significant bottleneck in genetics research.

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2010 Journal Article A. Prashanth, Wenzler, T., Tidwell, R., Bakunova, S. M., and Wilson, D. W., “Pharmacophore model for pentamidine analogs active against Plasmodium falciparum”, European Journal of Medicinal Chemistry, vol. 45, pp. 6147–6151, 2010.[Abstract]

Pentamidine and its analogs constitute a class of compounds that are known to be active against Plasmodium falciparum, which causes the most dangerous malarial infection. Malaria is a widespread disease known to affect hundreds of millions of people and presents a perceivable threat of spreading. Hence, there is a need for well-defined scaffolds that lead to new, effective treatment. Here we present a pentamidine-based pharmacophore constructed using GALAHAD that would aid targeted synthesis of leads with enhanced properties, as well as the development of lead scaffolds. The study was supported by high-quality biological in vitro data of 22 compounds against the P. falciparum strains NF54 and K1. The model established reveals the importance of hydrophobic phenyl rings with polar oxygen and amidine substituents and the hydrophobic linking chain for the activity against malaria.

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2009 Journal Article D. T. Okou, Locke, A. E., Steinberg, K. M., Hagen, K., Prashanth, A., Shetty, A. C., Patel, V., and Zwick, M. E., “Combining Microarray-based Genomic Selection (MGS) with the Illumina Genome Analyzer Platform to Sequence Diploid Target Regions”, Annals of Human Genetics, vol. 73, pp. 502–513, 2009.[Abstract]

Novel methods of targeted sequencing of unique regions from complex eukaryotic genomes have generated a great deal of excitement, but critical demonstrations of these methods efficacy with respect to diploid genotype calling and experimental variation are lacking. To address this issue, we optimized microarray-based genomic selection (MGS) for use with the Illumina Genome Analyzer (IGA). A set of 202 fragments (304 kb total) contained within a 1.7 Mb genomic region on human chromosome X were MGS/IGA sequenced in ten female HapMap samples generating a total of 2.4 GB of DNA sequence. At a minimum coverage threshold of 5X, 93.9% of all bases and 94.9% of segregating sites were called, while 57.7% of bases (57.4% of segregating sites) were called at a 50X threshold. Data accuracy at known segregating sites was 98.9% at 5X coverage, rising to 99.6% at 50X coverage. Accuracy at homozygous sites was 98.7% at 5X sequence coverage and 99.5% at 50X coverage. Although accuracy at heterozygous sites was modestly lower, it was still over 92% at 5X coverage and increased to nearly 97% at 50X coverage. These data provide the first demonstration that MGS/IGA sequencing can generate the very high quality sequence data necessary for human genetics research.

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2009 Journal Article A. Prashanth and W. Wilson, D., “Molecular Dynamics of Water-Mediated Interactions of a Linear Benzimidazole-Biphenyl Diamidine with the DNA Minor Groove”, Journal of American Chemical Society, vol. 131, p. 76, 2009.[Abstract]

DB921 has a benzimidazole−biphenyl system with terminal amidines that gives the compound a linear conformation with a radius of curvature that does not match the DNA minor groove shape. Surprisingly, the compound binds in the groove with an unusually high equilibrium constant [Miao, Y.; Lee, M. P. H.; Parkinson, G. N.; Batista-Parra, A.; Ismail, M. A.; Neidle, S.; Boykin, D. W.; Wilson, W. D. Biochemistry 2005, 44, 14701−14708]. X-ray crystallographic analysis of DB921 bound to −AATT− in d(CGCGAATTCGCG)2 showed that the benzimidazole is in position to directly interact with bases at the floor of the groove, while the phenylamidine of DB921 forms indirect contacts with the bases through an interfacial water. The DB921−water pair forms a curved, flexible module with a high Ka (or a low Kd) value of binding. To better understand the dynamics of the DB921−DNA complex and how water can be used in the design of compounds to recognize DNA, a 100 ns molecular dynamics simulation of the complex was conducted. In addition to the X-ray conformation, some significantly variant, dynamic conformations, which had additional interfacial water molecules between DB921 and DNA, appeared in the MD simulation. The benzimidazole contacts remained relatively constant through the entire simulation. The biphenylamidine end of the bound molecule, however, undergoes much larger changes in orientation relative to the floor of the groove as well as variations in the type of water interactions. The results provide an understanding of how water couples the linear DB921 compound to the minor groove for tight binding, without a large unfavorable contribution to the entropy of binding.

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2006 Journal Article A. Prashanth, Wenzler, T., Ruiz, P., Brun, R., Boykin, D. W., Tidwell, R., and W. Wilson, D., “3D QSAR on a library of heterocyclic diamidine derivatives with antiparasitic activity”, Bioorganic & Medicinal Chemistry, vol. 14, pp. 3144–3152, 2006.[Abstract]

African trypanosomes, Trypanosoma brucei rhodesiense (TBR) and Trypanosoma brucei gambiense (TBG), affect hundreds of thousands of lives in tropical regions of the world. The toxicity of the diamidine pentamidine, an effective drug against TBG, necessitates the design of better drugs. An orally effective prodrug of the diamidine, furamidine (DB75), presently scheduled for phase III clinical trials, has excellent activity against TBG with toxicity lower than that of pentamidine. As part of an effort to develop additional and improved diamidines against African trypanosomes, CoMFA and CoMSIA 3D QSAR analyses have been conducted with furamidine and a set of 25 other structurally related compounds. Two different alignment strategies, based on a putative kinetoplast DNA minor groove target, were used. Due to conserved electrostatic properties across the compounds, models that used only steric and electronic properties did not perform well in predicting biological results. An extended CoMSIA model with additional descriptors for hydrophobic, donor, and acceptor properties had good predictive ability with a q2 = 0.699, r2 = 0.974, SEE, standard error of estimate = 0.1, and F = 120.04. The results have been used as a guide to design compounds that, potentially, have better activity against African trypanosomes.

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Publication Type: Thesis
Year of Publication Publication Type Title
2008 Thesis A. Prashanth, “Application of Computer-Aided Drug Discovery Methodologies Towards the Rational Design of Drugs Against Infectious Diseases”, Georgia State University, Atlanta, Georgia, U. S. A, 2008.[Abstract]

Computer-aided drug discovery involves the application of computer science and programming to solve chemical and biological problems. Specifically, the QSAR (Quantitative Structure Activity Relationships) methodology is used in drug development to provide a rational basis of drug synthesis, rather than a trial and error approach. Molecular dynamics (MD) studies focus on investigating the details of drug-target interactions to elucidate various biophysical characteristics of interest. Infectious diseases like Trypanosoma brucei rhodesiense (TBR) and P. falciparum (malaria) are responsible for millions of deaths annually around the globe. This necessitates an immediate need to design and develop new drugs that efficiently battle these diseases. As a part of the initiatives to improve drug efficacy QSAR studies accomplished the formulation of chemical hypothesis to assist development of drugs against TBR. Results show that CoMSIA 3D QSAR models, with a Pearson’s correlation coefficient of 0.95, predict a compound with meta nitrogens on the phenyl groups, in the combinatorial space based on a biphenyl-furan diamidine design template, to have higher activity against TBR relative to the existing compound set within the same space. Molecular dynamics study, conducted on a linear benzimidazole-biphenyl diamidine that has non-classical structural similarity to earlier known paradigms of minor groove binders, gave insights into the unique water mediated interactions between the DNA minor groove and this ligand. Earlier experiments suggested the interfacial water molecules near the terminal ends of the ligand to be responsible for the exceptianlly high binding constant of the ligand. Results from MD studies show two other modes of binding. The first conformation has a single water molecule with a residency time of 6ns (average) that is closer to the central part of the ligand, which stabilizes the structure in addition to the terminal water. The second conformation that was detected had the ligand completely away from the floor of the minor groove, and hydrogen bonded to the sugar oxygens.

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Publication Type: Conference Paper
Year of Publication Publication Type Title
2006 Conference Paper A. Prashanth, Tidwell, R. R., and W Wilson, D., “Computational target validation based on 3-D QSAR for antiparasitic leads”, in American Chemical Society National Meeting, 1155 16TH ST, NW, WASHINGTON, DC 20036 USA, 2006.[Abstract]

Pentamidine has been known to be active against a range of parasitic diseases including the malarial parasite which causes millions of deaths per year. There are two separate schools with regard to the primary target involved with the activity of this compound in P. falciparum - DNA minor groove, ferritoporphyrin IX (FPIX). This study aims at working with available pentamidine analogs in our database that are active against malaria to develop a probabilistic model that will be able to computationally evaluate target complementarity. Our protocol to develop such a model is to use GASP for conformational analysis and develop pharmacophore hypothesis followed by 3D QSAR to assist in target validation. Usage of pentamidine against diseases is prone to problems with respect to toxicity and oral availability. Target validation would open new pathways in terms of developing effective leads against Malaria and/or guide the synthesis of other scaffolds.

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