DEVELOPMENT OF PHARMACOPHORE MODELS FOR PREDICTING HIV-1 REVERSE TRANSCRIPTASE INHIBITORY ACTIVITY OF PYRIDINONE DERIVATIVES

In order to understand the essential structural features of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT) inhibitors, three-dimensional (3D) pharmacophore hypotheses were built based on a set of known HIV-1 RT inhibitors selected from literature using PHASE program. Ten four-point 3D pharmacophore models, each with one hydrogen bond acceptor (A), one hydrogen bond donor (D), one hydrophobic group (H), and one aromatic ring (R) as pharmacophore features were developed. Among these, the hypothetical pharmacophore ADHR1 yielded a statistically significant hypothesis with correlation coefficient R(2) = 0.918 value, which was considered to be the best pharmacophore hypothesis. The developed pharmacophore hypothesis was externally validated by predicting the activity of test set molecules. The squared predictive correlation coefficient of 0.743 was observed between experimental and predicted activity values of test set molecules. The geometry and features of pharmacophore hypothesis were expected to be useful for the design of selective HIV-1 RT inhibitors.