Structure-Based Alignment and Comparative Molecular Field Analysis of Acetylcholinesterase Inhibitors

• Published in: Journal of medicinal chemistry 1996-12, Vol.39 (26), p.5064-5071
• Main Authors: Cho, Sung Jin, Garsia, Maria Luisa Serrano, Bier, Jim, Tropsha, Alexander
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - drug effects; Binding Sites; Biological and medical sciences; Cholinesterase Inhibitors - chemistry; General pharmacology; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm950771r

The method of comparative molecular field analysis (CoMFA) was used to develop quantitative structure−activity relationships for physostigmine, 9-amino-1,2,3,4-tetrahydroacridine (THA), edrophonium (EDR), and other structurally diverse inhibitors of acetylcholinesterase (AChE). The availability of the crystal structures of enzyme/inhibitor complexes (EDR/AChE, THA/AChE, and decamethonium (DCM)/AChE) (Harel, M.; et al. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 9031−9035) provided information regarding not only the active conformation of the inhibitors but also the relative mutual orientation of the inhibitors in the active site of the enzyme. Crystallographic conformations of EDR and THA were used as templates onto which additional inhibitors were superimposed. The application of cross-validated R 2 guided region selection method, recently developed in this laboratory (Cho, S. J.; Tropsha, A. Cross-Validated R2 Guided Region Selection for Comparative Molecular Field Analysis (CoMFA):  A Simple Method to Achieve 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.