A 3D QSAR STUDY OF A SERIES OF HEPT ANALOGS - THE INFLUENCE OF CONFORMATIONAL MOBILITY ON HIV-1 REVERSE-TRANSCRIPTASE INHIBITION

Quantitative structure-activity relationships (QSAR) have been establi shed for 87 analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thy mine (HEFT), a potent inhibitor of the HIV-1 reverse transcriptase (RT ). Of these 87 nonnucleoside RT inhibitors, 9 novel HEFT analogues wer e used in the study and the others were taken from the literature. The predictive ability of these relationships has been evaluated using a large set of 54 compounds which were not used to derive the activity m odel. Descriptors related to the conformational changes were found to be an important factor which underlies RT inhibitory activity in the H EFT series. Indeed, the QSAR model provides evidence concerning the co nformational transformations the molecules may undergo during the inhi bition process. The established relationships are supplementary to the experimental study on the binding of HEFT type inhibitors to RT by Ho pkins et al. (J. Med. Chem. 1996, 39, 1589-1600). The present study su ggests a quantitative interpretation of the structure-activity relatio nships which otherwise cannot be explained within the framework of the crystal inhibitor-protein model. This information is pertinent to the further design of new HEFT type RT inhibitors.