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Identification of 1 H ‐indene‐(1,3,5,6)‐tetrol derivatives as potent pancreatic lipase inhibitors using molecular docking and molecular dynamics approach
Author(s) -
Kalathiya Umesh,
Padariya M.,
Baginski M.
Publication year - 2015
Publication title -
biotechnology and applied biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 70
eISSN - 1470-8744
pISSN - 0885-4513
DOI - 10.1002/bab.1432
Subject(s) - docking (animal) , indene , molecular dynamics , chemistry , indole test , stereochemistry , autodock , scaffold , lipase , molecular model , enzyme , computational biology , combinatorial chemistry , biochemistry , computational chemistry , biology , in silico , computer science , organic chemistry , database , medicine , nursing , gene
Pancreatic lipase is a potential therapeutic target to treat diet‐induced obesity in humans, as obesity‐related diseases continue to be a global problem. Despite intensive research on finding potential inhibitors, very few compounds have been introduced to clinical studies. In this work, new chemical scaffold 1 H ‐indene‐(1,3,5,6)‐tetrol was proposed using knowledge‐based approach, and 36 inhibitors were derived by modifying its functional groups at different positions in scaffold. To explore binding affinity and interactions of ligands with protein, CDOCKER and AutoDock programs were used for molecular docking studies. Analyzing results of rigid and flexible docking algorithms, inhibitors C_12, C_24, and C_36 were selected based on different properties and high predicted binding affinities for further analysis. These three inhibitors have different moieties placed at different functional groups in scaffold, and to characterize structural rationales for inhibitory activities of compounds, molecular dynamics simulations were performed (500 nSec). It has been shown through simulations that two structural fragments (indene and indole) in inhibitor can be treated as isosteric structures and their position at binding cleft can be replaced by each other. Taking into account these information, two lines of inhibitors can further be developed, each line based on a different core scaffold, that is, indene/indole.