Quantitative structure-activity relationships by distance geometry: systematic analysis of dihydrofolate reductase inhibitors

Abstract

Extensions are presented for the distance geometry approach to rationalizing ligand binding data. These are algorithms to detect when homologs are not binding with the same orientation in the binding site, but they are chemically similar; to deduce what the binding site''s size and shape must be and to calculate the optimal set of interaction energies between parts of the site and parts of the ligand molecules. This improved methodology is tested on a set of 68 quinazoline inhibitors of Streptococcus faecium dihydrofolate reductase. Results are discussed and compared with the Hansch method of QSAR [quantitative structure-activity relationship] and an improved inhibitor is predicted.