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Online Journal of Bioinformatics©
Sriramamurthy Boppanaa, Nataraj Sekhar Pagadalab and Kanchugarakoppal S Rangappab.
aDepartment of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore-570006, bDepartment of Genetics, Osmanai University, Hyderabad, India
Boppana S, Pagadala NS, Rangappa KS., In silico inhibition of acetylcholine esterase in Alzheimer’s, Onl J Bioinform., 20(3): 210-220, 2019. Structure-based generation of a novel series of acetylcholine esterase (AchE) inhibitors were carried out with the crystal structure of acetylcholine esterase complexed with choline (PDB: 2HA3) obtained from protein data bank. Docking studies performed on crystal structure of acetylcholine esterase with choline (PDB: 2HA3) identified a number of potent and selective AchE inhibitors. These molecules were designed by substituting different chemical groups on imidazo [1,2-a] pyridine-8-carboxamide replacing 1 H-indene group in rutacarpine with different groups like 2-(2-oxo-2H-chromen-3-yl) imidazo [1,2-a] pyridine-8-carboxamide, N-methyl-2- (2-thienyl) imidazo [1,2-a] pyridine-8-carboxamide, imidazo [1,2-a] pyridine-8-carboxamide, 2-(2-furyl) imidazo [1,2-a] pyridine-8-carboxamide, 2-(4-nitrophenyl) imidazo [1,2-a] pyridine-8-carboxamide, 2-(4-methoxyphenyl) imidazo [1,2-a] pyridine-8-carboxamide, and 2-(3,4-dichlorophenyl)imidazo[1,2-a]pyridine-8-carboxamide. Several scoring functions were evaluated using OPENEYE software and the protein-ligand interaction score (total score) was correlated to pIC50. The results indicated that these molecules have good binding affinity towards mouse AChE enzyme. Docking studies show that there is a general binding mode for nearly all compounds interacting with Tyr338 halfway down the gorge, and Tyr341 at the peripheral anionic site at the mouth of the gorge. The criteria for selecting compounds having greater chance of activity were developed by these protein-ligand interaction scores, predicted binding modes and key protein-ligand interactions. Our studies thus may help in designing synthetic drugs.
Keywords: Acetylcholine esterase, Structure based drug designing, Alzheimer’s disease.