Comparative molecular moment analysis (CoMMA): 3D-QSAR without molecular superposition

3d-QSAR procedures utilize descriptors that characterize molecular shape and charge distributions responsible for the steric and electrostatic nonbonding interactions intimately involved in ligand-receptor binding. Comparative molecular moment analysis (CoMMA) utilizes moments of the molecular mass and charge distributions up to and including second order in the development of molecular similarity descriptors. As a consequence, two Cartesian reference frames are then defined with respect to each molecular structure. One frame is the principal inertial axes calculated with respect to the center-of-mass. For neutrally charged molecular species, the other reference frame is the principal quadrupolar axes calculated with respect to the molecular "center-of-dipole." QSAR descriptors include quantities that characterize shape and charge independently as well as quantities that characterize their relationship. 3D-QSAR partial least squares (PLS) cross-validation procedures are utilized to predict the activity of several training sets of molecules previously investigated. This is the first time that molecular electrostatic quadrupolar moments have been utilized in a 3D-QSAR analysis, and it is shown that descriptors involving the quadrupolar moments and related quantities are required for the significant cross-validated predictive r2's obtained. CoMMA requires no superposition step, i.e., no step requiring a comparison between two molecules at any stage of the 3D-QSAR calculation.