Application of MS-WHIM Descriptors: 1. Introduction of New Molecular Surface Properties and 2. Prediction of Binding Affinity Data

Abstract

New 3D theoretical descriptors named MS-WHIM were recently developed by applying the WHIM approach to Molecular Surface points. The unitary value and the electrostatic potential, calculated onto every surface point, were initially used as properties to obtain information about size, shape and electrostatic distribution of a molecule. We have introduced new properties related to hydrogen bonding capacity and hydrophobicity. Expanded MS-WHIM descriptors were applied to model i) the binding affinity of 16 coumarin type substrates and inhibitors of cytochrome P4502A5, and ii) the binding affinity of 78 polyhalogenated aromatic compounds to cytosolic Ah receptor. PLS regressions were derived and validated through cross-validation and repeated scrambling of the response variable. Cross-validated results based on original properties (q2=0.573 and q2=0.698, for series (i) and (ii) respectively) were comparable to those reported in the literature using CoMFA fields. The introduction of the new molecular surface properties only slightly improved the results (q2=0.584 and q2=0.710). The application of a property selection strategy, however, yielded significant improvements. The additional properties were retained in the best models found (q2=0.706 and q2=0.732). The contribution of each molecular surface property was computed and aided the interpretation of the models.