Different electrostatic descriptors in comparative molecular field analysis: A comparison of molecular electrostatic and coulomb potentials

Abstract

Comparative molecular field analysis (CoMFA) is a three-dimensional quantitative structure-activity relationship (3D-QSAR) method which correlates precalculated fields surrounding a set of molecules with some target property. Among others, the electrostatic fields are commonly used. These are usually generated by calculating the Coulomb potential between a probe and the molecules bearing atom-centered point charges. The present study was performed in order to investigate up to which extent different methods to calculate electrostatic potentials can influence the results of a CoMFA. Therefore, a variety of charge calculation methods was applied to a data set consisting of 37 ligands of the benzodiazepine receptor inverse agonist-antagonist active site. These methods included Gasteiger-Marsili, semiempirical (MNDO, AM1, and PM3), and ab initio (HF/STO-3G, HF/3-21G*, and HF/6-31G*) charges. Semiempirical as well as ab initio electron populations were derived both from the Mulliken population analysis (MPA) or from fitting the charges to the molecular electrostatic potential (ESPFIT charges). In addition, the molecular electrostatic potentials (MEPs) resulting from ab initio calculations were mapped directly onto the CoMFA grid. With regard to the cross-validated r2 values (r2cv) of the resulting QSAR models, the ESPFIT-derived potentials yielded generally higher r2cv values than those resulting from MPA charges. For example, at the HF/3-21G* level the r2cv rose from 0.61 (MPA-derived potentials) to 0.76 (ESPFIT fields). The MEPs mapped directly onto the CoMFA grid were not superior to the corresponding ESPFIT-derived potentials. Semiempirical ESPFIT charges appeared to be of similar quality compared with ab initio ESPFIT electron populations in the CoMFAs. When no scaling between the steric and electrostatic descriptor matrices was applied, the electrostatic contributions were influenced to a high degree by the magnitude of the corresponding field values. © 1996 by John Wiley & Sons, Inc.