Polarizability Fields for Use in Three-Dimensional Quantitative Structure−Activity Relationship (3D-QSAR)

Abstract

Comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (3D-QSAR) technique, has proven to be a valuable tool in the field of rational drug design. In its native form, CoMFA utilizes a pseudoreceptor, in the form of a regularly spaced lattice of probe atoms, to characterize the steric and electrostatic properties of a series of mutually superimposed molecules. Statistical analyses are performed in an attempt to correlate changes in these shape and charge related fields to observed differences in biological activities at a given target. Graphical analyses of the resulting "negative receptor images" have been demonstrated to provide insight into the physicochemical requirements of novel ligands. Several groups have previously demonstrated the benefits of additional or alternative fields for these types of analyses. In this report, a novel molecular potential field derived from atomistic contributions to molecular polarizability is presented. Comparison studies will be presented using literature data sets and CoMFA models derived from steric, electrostatic, and polarizability fields. The overall conclusion is that molecular polarizability fields derived from semiempirically determined atomic polarizabilities are highly predictive and graphically descriptive supplements to, and perhaps surrogates for, the standard CoMFA steric and electrostatic fields.