LY-73497

Human immunodeficiency virus type-1 (HIV-1) is a pathogenic retrovirus and the causative agent of acquired immunodeficiency syndrome (AIDS).HIV-1 RT is one of the key enzymes in the duplication of HIV-1.Inhibitors of HIV-1 RT are classified as nonnucleoside reverse transcriptase inhibitors (NNRTIs) and NRTIs.NNRTIs bind in a region not associated with the active site of the enzyme.Within the NNRTIs category, there is a set of inhibitors commonly referred to as Ph or pyridyl Et thiourea (PET) derivativesThe present three-dimensional (3D) quant. structure-activity relationship (QSAR) study attempts to explore the structural requirements of (Ph Et thiourea) PET derivatives for anti-HIV activity.Based on the structures and biodata of previous PET analogs, comparative mol. similarity indexes anal. (CoMSIA) is performed to explain the structural requirements for the anti-HIV activity of PET derivativesThe CoMSIA studies resulted in reliable computational models.The obtained CoMSIA model has high predictive ability, q² = 0.584, r² = 0.882 and standard error of estimation (SEE) = 0.352, explaining the majority of the variance in the data with four partial least square (PLS) components.The predictive ability of the developed models (3D QSAR) was also confirmed by using a test (external validation) set comprised of 11 mols. with a predicted r² value of 0.871.It is shown that the steric, electrostatic, hydrophobic, and hydrogen-bond acceptor and donor properties predicted by CoMSIA contours can be related to anti-HIV activity.This model is a significant guide to trace the features that really matter especially with respect to the design of novel compoundsComparative mol. similarity indexes anal. for predicting anti-HIV activity of Ph Et thiourea (PET) derivativesThe parameters indicated in the substitution position of compound are responsible for anti-HIV activity.

In this work, an efficient strategy was presented to search drug leads for human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) using hierarchical database screenings, which included a pharmacophore model, multiple-conformation rigid docking, solvation docking, and molecular mechanics-Poisson-Boltzmann/surface area (MM-PB/SA) sequentially. Encouraging results were achieved in searching a refined available chemical directory (ACD) database: the enrichment factor after the first three filters was estimated to be 25-fold; the hit rate for all the four filters was predicted to be 41% in a control test using 37 known HIV-1 non-nucleoside reverse transcriptase inhibitors; 10 out of 30 promising solvation-docking hits had MM-PB/SA binding free energies better than -6.8 kcal/mol and the best one, HIT15, had -17.0 kcal/mol. In conclusion, the hierarchical multiple-filter database searching strategy is an attractive strategy in drug lead exploration.