HIV‐1 reverse transcriptase (RT) is one of the most important enzymes required for viral replication, thus acting as an attractive target for antiretroviral 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 .8078, cross‐validated value of 0.5397 for training set and Q² of 0.4669, Pearson's r of .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 and (ii) hydrogen bond with residue Lys101 and halogen bond with residue Tyr188. The pharmacophore features of six‐point hypothesis AADRRR.184, AAADRR.38, and 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.

中文翻译：

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基于对接场的QSAR和药效基团研究靶向HIV-1逆转录酶的取代嘧啶衍生物

HIV-1逆转录酶（RT）是病毒复制所需的最重要的酶之一，因此成为抗逆转录病毒疗法的诱人靶标。据报道，嘧啶类似物在我们以前的研究中对HIV-1 RT具有选择性抑制作用，并具有良好的抗病毒活性。为了进一步探索抑制活性与药效学特征之间的关系，使用Schrodinger Suite生成并验证了基于现场的QSAR模型（​​相关系数为.8078，训练集的交叉验证值为0.5397，Q ²为0.4669，Pearson's r测试集的.7357）。还研究了对接，口袋表面和药效团研究来定义结合模式和药效团特征，包括（i）与残基Tyr181，Tyr188和Trp229的π-π相互作用以及与His235的p-π相互作用以及（ii）与H235的氢键相互作用。残基Lys101和卤素与残基Tyr188键合。六点假设AADRRR.184，AAADRR.38和AADRRR.26的药效基团特征进一步完善了对接和QSAR结果。我们还发现，蛋白质-配体复合物表现出较高的相对结合自由能。这些观察结果可能被用来指导新型HIV-1 RT抑制剂的合理设计和优化。