Document Report Card

ID: ALA1123744

Journal: J Med Chem

Title: A quantitative structure-activity relationship analysis of some 4-aminodiphenyl sulfone antibacterial agents using linear free energy and molecular modeling methods.

Authors: Lopez de Compadre RL, Pearlstein RA, Hopfinger AJ, Seydel JK.

Abstract: A set of 36 congeneric 4-aminodiphenyl sulfones with measured inhibition potencies of dihydropteroate synthase were studied by using both linear free energy and molecular modeling methods. The goals of the investigation were to identify the "active" conformation for these compounds as inhibitors and, correspondingly, to contruct a quantitative structure-activity relationship (QSAR). These molecules are quite flexible and possess multiple conformational energy minima. Application of molecular shape analysis (MSA), using all intramolecular energy minima as part of the analysis, was not successful in generating a QSAR. However, the calculated intramolecular conformational entropy of these compounds was found to correlate with inhibition potency leading to a highly significant QSAR. Inhibition potency increases as entropy decreases. A decrease in entropy enhances the population of specific, symmetry-related minimum-energy conformations. In this indirect way, it was possible to postulate an "active" conformation. This investigation illustrates that specific knowledge of the "active" shape of a molecule may not provide the information needed to quantitatively explain the observed structure-activity relationship.

CiteXplore: 3572979

DOI: 10.1021/jm00388a026