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

Abstract

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 R2 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 q2 of 0.734.

Catalytic Self‐Screening of Cholinesterase Substrates from a Dynamic Combinatorial Thioester Library

“…This long lag phase may be caused by inhibitory activities of the present esters. [23] All the other acyl groups remained untouched by the enzyme, a result which is in accordance with the known specificity of acetylcholinesterase. Addition of the enzyme after complete equilibration of the library, as compared to addition of enzyme from the beginning, did not result in any major differences and the same distribution of compounds was recorded, as had been anticipated.…”

Building a Bridge between G-Protein-Coupled Receptor Modelling, Protein Crystallography and 3D QSAR Studies for Ligand Design

“…However, when the alignment is based on the target protein structure, as in this study, there may be certain correlations. Cho et al [77] claimed that the location of the contour coefficient maps was consistent with what was known about the active site of AChE; the sterically favorable regions occupied cavities in the AChE active site, whereas the sterically unfavorable regions overlapped with enzyme atoms.…”

“…Cho et al [77] used the three available enzyme-inhibitor complex structures to align a series of 60 chemically diverse acetylcholinesterase inhibitors, shown below:…”

3D-QSAR Applied to the Quantitative Prediction of Penicillin G Amidase Selectivity

“…[7] Unlike the classical 3D-QSAR approach, such as the CoMFA method, [8] the GRIND and the Volsurf methods present the major advantage of being independent from any alignment of molecules, which is usually a primary source of error in this kind of studies. [9,10] The experimental data set (DS19) includes the k cat /K M values for the hydrolysis of 19 substrates presenting a quite broad structural variability comprising seven blactam compounds, ten N-phenylacetyl amino acids, one anilide and one ester (Table 1). Within these substrates, a sub-set made of only 10 structures (DS10) was defined (Table 1), in order to verify the possibility to build up the models on the basis of a restricted training data set.…”