REPLACEMENT OF STERIC 6-12 POTENTIAL-DERIVED INTERACTION ENERGIES BY ATOM-BASED INDICATOR VARIABLES IN COMFA LEADS TO MODELS OF HIGHER CONSISTENCY

The steric descriptors commonly used in CoMFA - Lennard-Jones 6-12 potential-derived interaction energies calculated between a probe atom and the molecules under investigation - have been replaced by variables indicating the presence of an atom of a particular molecule in predefined volume elements (cubes) within the region enclosing the ensemble of superimposed molecules. The resulting 'atom indicator vectors' were used as steric fields in the subsequent PLS analyses, with and without inclusion of electrostatic Coulomb interaction-derived fields. Application of this method to five training sets (80 compounds each) and five test sets (60 compounds each), randomly selected from an ensemble of 256 dihydrofolate reductase inhibitors, leads to models of significantly higher consistency, as indicated by the cross-validated r(2) values for the training sets and the predictive r(2) values for the test sets.