关键词: HIV-1逆转录酶, S-DABOs, 分子对接, 基于场的三维定量构效关系

Abstract:

HIV-1 reverse transcriptase (RT) inhibitors are major components of HAART (highly active antiviral therapy). The S-DABOs (dihydro-alkylthio-benzyl-oxopyrimidines) series and their similar skeletons have exhibited preferable activities to inhibit HIV-1 RT. In the present study, we generated field-based QSAR models using common structure alignment, which was characterized by Gaussian steric, electrostatic, hydrophobic, hydrogen bond donor, hydrogen bond acceptor and aromatic ring fields (R² = 0.8421, R²_CV = 0.5949 for the training set, Q² = 0.5486, Pearson-r = 0.7460 for the test set). Docking, pocket surface and contourmap analyses were carried out. Key pharmacophore features were investigated, including (i) π-π interaction with residue Tyr181, Tyr188 and Trp229, σ-π interaction with His236, (ii) hydrogen bond with residue Lys101 and halogen bond with residue Tyr188. The docking analysis and field-based QSAR models could provide reasonable guidance in the rational design of potent HIV-1 RT inhibitors.

Key words: HIV-1 reverse transcriptase, S-DABOs, Molecular docking, Field-based QSAR