Docking Field-based QSAR and pharmacophore studies on the substituted pyrimidine derivatives targeting HIV-1 reverse transcriptase

Abstract

HIV-1 reverse transcriptase (RT) is one of the most important enzymes required for viral replication, thus acting as an attractive target for anti-retroviral therapy. Pyrimidine analogues reportedly have selective inhibition on HIV-1 RT with favorable antiviral activities in our previous study. To further explore the relationship between inhibitory activity and pharmacophoric characteristics, field-based QSAR models were generated and validated using Schrodinger Suite (correlation coefficient of 0.8078, cross-validated value of 0.5397 for training set and Q² of 0.4669, Pearson-r of 0.7357 for test set). Docking, pocket surfaces and pharmacophore study were also investigated to define the binding pattern and pharmacophoric features, including (i) π-π interaction with residue Tyr181, Tyr188 and Trp229 and p-π interaction with His235 (ii) hydrogen bond with residue Lys101 and halogen bond with residue Tyr188. The pharmacophore features of six-point hypothesis AADRRR.184, AAADRR.38, AADRRR.26 further complimented to the docking and QSAR results. We also found that the protein-ligand complex exhibited high relative binding free energy. These observations could be potentially utilized to guide the rational design and optimization of novel HIV-1 RT inhibitors.

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The results of 3D-QSAR, binding pocket and pharmacophore analyses of pyrimidine HIV-1 RT inhibitors would rationally clarify 3D-QSAR and pharmacophore features of pyrimidine analogues and help in the design the potential inhibitors of HIV-1 RT.

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