Docking analysis of a series of benzylamino acetylcholinesterase inhibitors with a phthalimide, benzoyl, or indanone moiety.

The enzyme-binding mode of a series of acetylcholinesterase inhibitors has been analyzed on the basis of the crystal structure of the Torpedo enzyme using docking programs DOCK and directed-DOCK. The inhibitors have a benzyl group connected to tertiary ammonium nitrogen at one end and a phthalimide, benzoyl, or indanone moiety at the other. Our modeling results have indicated that the benzyl group interacts with Trp 84, which is located near the bottom of the binding pocket and is postulated to be the quaternary ammonium binding site for acetylcholine. The other aromatic ring has been found to interact with Trp 279 at the peripheral hydrophobic site. In addition, the hydrogen-bonding interaction between a carbonyl group of the inhibitor and Tyr 121 OH seems to play an important role. Our active-orientation model is, at least qualitatively, consistent with structure-activity data for more than 50 compounds and should be useful for the design of more potent inhibitors.