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Publication Type : Journal Article
Publisher : Arch Pharm (Weinheim)
Source : Arch Pharm (Weinheim), Volume 352, Issue 10, p.e1900029 (2019)
Url : https://pubmed.ncbi.nlm.nih.gov/31407389/
Keywords : Animals, drug design, Enzyme Inhibitors, Humans, Lethal Dose 50, Lipase, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Structure, pancreas, Protein Binding, Rhodanine, Structure-Activity Relationship
Campus : Kochi
School : School of Pharmacy
Department : Pharmaceutical Chemistry & Analysis
Year : 2019
Abstract : A series of rhodanine-3-acetic acid derivatives were synthesized via Knoevenagel condensation of rhodanine-3-acetic acid with various substituted aromatic aldehydes. The synthesized derivatives were screened in vitro for understanding the inhibitory potential towards pancreatic lipase (PL), a key enzyme responsible for the digestion of dietary fats. Derivative 8f exhibited a potential inhibitory activity towards PL (IC = 5.16 µM), comparable to that of the standard drug, orlistat (0.99 µM). An increase in the density of the aromatic ring resulted in potential PL inhibition. The enzyme kinetics of 8f exhibited a reversible competitive-type inhibition, similar to that of orlistat. Derivative 8f exhibited a MolDock score of -125.19 kcal/mol in docking studies, and the results were in accordance with their PL inhibitory potential. Furthermore, the reactive carbonyl group of 8f existed at a distance adjacent to Ser152 (≈3 Å) similar to that of orlistat. Molecular dynamics simulation (10 ns) of the 8f-PL complex revealed a stable binding conformation of 8f in the active site of PL (maximum root mean square displacement of ≈2.25 Å). The present study identified novel rhodanine-3-acetic acid derivatives with promising PL inhibitory potential, and further lead optimization might result in potent PL inhibitors.
Cite this Research Publication : Divya Chauhan, Ginson George, Sridhar S. N. C., Rohit Bhatia, Atish T. Paul, and Vikramdeep Monga, “Design, synthesis, biological evaluation, and molecular modeling studies of rhodanine derivatives as pancreatic lipase inhibitors.”, Arch Pharm (Weinheim), vol. 352, no. 10, p. e1900029, 2019.