Charged partial surface area (CPSA) descriptors QSAR applications.

Abstract

The charged partial surface area, or CPSA descriptors were originally designed for use in structure-physical relationship studies to capture information about the features of molecules responsible for polar intermolecular interactions. Since their development, they have found applications in a broad variety of both structure-property and structure-activity relationship studies. In the present work, the CPSA descriptors are examined in more detail, evaluating their characteristics with regard to conformational dependence, sources of partial atomic charges, utility of whole molecule and substructure varieties, and the inclusion or exclusion of explicit hydrogens. Additionally, an examination of the physical interpretation that can be derived from structure-activity relationships that incorporate the CPSA descriptors is made. Most recently, the CPSA descriptors have been found to be practically useful in the study of acute aquatic toxicity where they appear to provide an alternative to LUMO energy level measures for describing global and local electrophilicity in cases of non-covalent molecular interactions. A second example illustrates the ability of the CPSA descriptors to discriminate agonists and antagonists among compounds that bind strongly at the estrogen receptor. While measures of global and local nucleophilicity and interatomic distances are required to explain receptor binding, volumetric parameters, such as CPSAs, were found to be necessary to provide separation between reactivity patterns for agonists and antagonists, all having high binding affinity to estrogen receptor.