STRUCTURE-BASED ALIGNMENT AND COMPARATIVE MOLECULAR-FIELD ANALYSIS OFACETYLCHOLINESTERASE INHIBITORS

The method of comparative molecular field analysis (CoMFA) was used to develop quantitative structure-activity relationships for physostigmi ne, 9-amino-1,2,3,4-tetrahydroacridine (THA), edrophonium (EDR), and o ther structurally diverse inhibitors of acetylcholinesterase (AChE). T he availability of the crystal structures of enzyme/inhibitor complexe s (EDR/AChE, THA/ AChE, and decamethonium (DCM)/AChE) (Harel, M.; et a l. Quaternary ligand binding to aromatic residues in the active-site g orge of acetylcholinesterase. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 9031-9035) provided information regarding not only the active conforma tion of the inhibitors but also the relative mutual orientation of the inhibitors in the active site of the enzyme. Crystallographic conform ations of EDR and THA were used as templates onto which additional inh ibitors were superimposed. The application of cross-validated R(2) gui ded region selection method, recently developed in this laboratory (Ch o, S. J.; Tropsha, A. Cross-Validated R(2) Guided Region Selection for Comparative Molecular Field Analysis (CoMFA): A Simple Method to Achi eve Consistent Results. J. Med. Chem. 1995, 38, 1060-1066), to 60 AChE inhibitors led to a highly predictive CoMFA model with the q(2) of 0. 734.