Application of MS-WHIM descriptors: 1. Introduction of new molecular surface properties and 2. Prediction of binding affinity data

New 3D theoretical descriptors named MS-WHIM were recently developed by app lying the WHIM approach to Molecular Surface points. The unitary value and the electrostatic potential, calculated onto every surface point, were init ially used as properties to obtain information about size, shape and electr ostatic distribution of a molecule. We have introduced new properties relat ed to hydrogen bonding capacity and hydrophobicity. Expanded MS-WHIM descri ptors were applied to model i) the binding affinity of 16 coumarin type sub strates and inhibitors of cytochrome P4502A5, and ii) the binding affinity of 78 polyhalogenated aromatic compounds to cytosolic Ah receptor. PLS regr essions were derived and validated through cross-validation and repeated sc rambling of the response variable. Cross-validated results based on origina l properties (q(2) = 0.573 and q(2) = 0.698, for series (i) and (ii) respec tively) were comparable to those reported in the literature using CoMFA fie lds. The introduction of the new molecular surface properties only slightly improved the results (q(2) = 0.584 and q(2) = 0.710). The application of a property selection strategy, however, yielded significant improvements. Th e additional properties were retained in the best models found (q(2) = 0.70 6 and q(2) = 0.732). The contribution of each molecular surface property wa s computed and aided the interpretation of the models.