Theory and application of molecular potential energy fields in molecular shape analysis: a quantitative structure--activity relationship study of 2,4-diamino-5-benzylpyrimidines as dihydrofolate reductase inhibitors.

A general formalism, based upon molecular mechanics pairwise potential functions, has been developed to compute the molecular potential energy fields inherent to a given molecule in a given conformation. Molecular descriptors are derived from the potential energy fields, which can be used in QSAR studies based upon molecular shape analysis. These descriptors have been computed for a set of 2,4-diamino-5-benzylpyrimidines that are dihydrofolate reductase (DHFR) inhibitors. A QSAR is derived in which DHFR inhibition activity can be explained in terms of molecular shape, as represented by differences in molecular potential energy fields between pairs of superimposed molecules, and the sum of the pi constants of substituents on the 3- and 4-position of the benzyl ring. This QSAR is superior to one developed earlier (Hopfinger, A. J. J. Med. Chem. 1981, 24, 818) in which molecular shape is described by common overlap steric volume. Ancillary information defining the "active" conformation and electrostatic nature of the binding site are realized in the construction of the QSAR.