PREDICTION OF THE BINDING-SITE OF 4-[(5,6-DIMETHOXY-1-INDANON-2-YL)METHYL]PIPERIDINE IN ACETYLCHOLINESTERASE BY DOCKING STUDIES WITH THE SYSDOC PROGRAM

In the preceding paper we reported on a docking study with the SYSDOC program for predicting the binding sites of huperzine A in acetylcholi nesterase (AChE) [Pang, Y.-P. and Kozikowski, A.P., J. Comput.-Aided M el. Design, 8 (1994) 669]. Here we present a prediction of the binding sites of 4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine (E2020) i n AChE by the same method, E2020 is one of the most potent and selecti ve reversible inhibitors of AChE, and this molecule has puzzled resear chers, partly due to its flexible structure, in understanding how it b inds to AChE. Based on the results of docking 1320 different conformer s of E2020 into 69 different conformers of AChE and on the pharmacolog ical data reported for E2020 and its analogs, we predict that both the R- and the S-isomer of E2020 span the whole binding cavity of AChE, w ith the ammonium group interacting mainly with Trp(84), Phe(330) and A sp(72) the phenyl group interacting mainly with Trp(84) and Phe(330), and the indanone moiety interacting mainly with Tyr(70) and Trp(279). Th, topography of the calculated E2020 binding sites provides insights into understanding the high potency of E2020 in the inhibition of ACh E and provides hints as to possible structural modifications for ident ifying improved AChE inhibitors as potential therapeutics for the pall iative treatment of Alzheimer's disease.