The comparative molecular surface analysis (COMSA): a novel tool for molecular design

A new method allowing for 3-D QSAR analysis and the prediction of biologica l activity is presented. Unlike comparative molecular field analysis (CoMFA )-like techniques, it is based not on a comparison of the properties charac terizing a discrete set of points but on the mean electrostatic potential ( MEP) calculated and labeling specific areas defined on the molecular surfac e. A Kohonen self-organizing neural network and partial least square (PLS) analysis have been used for performing such an operation. The series of ste roids complexing the corticosteroid (CBG) and testosterone (TBG) globulins, which forms a benchmark measuring the performance of the methods in molecu lar design, and a series of benzoic acids described by the Hammett sigma co nstants is used For testing the method. It is demonstrated that a method ca n be used efficiently to evaluate the responses determined both by the comb ination of electrostatic and steric effects or by electrostatic effects alo ne, therefore, two different schemes were developed. The first one, which i nvolves PLS analysis of the full comparative networks, covers both steric a nd electrostatic effects. This scheme works well for both the CBG and TBG d ata. The second scheme takes into account only the properties (MEP) of thes e regions within molecules that can be superimposed with the template molec ule. This scheme provides the best predictive power for the benzoic acids s eries. Comparison of the results from a CoMFA analysis proves that method i s at least as effective for the responses limited by electrostatic effects, although it significantly outperforms CoMFA for CBG affinity which is domi nated by steric effects. (C) 2000 Elsevier Science Ltd. All rights reserved .