Introduction: Inhibition of the reverse transcriptase (RT) enzyme of the human immunodeficiency virus (HIV) by low molecular weight inhibitors is still an active area of research. Here, protein-ligand interactions and possible binding modes of novel compounds with the HIV-1 RT binding pocket (the wild-type as well as Y181C and K103N mutants) were obtained and discussed.

Methods: A molecular fragment-based approach using FDA-approved drugs were followed to design novel chemical derivatives using delavirdine, efavirenz, etravirine and rilpivirine as the scaffolds. The drug-likeliness of the derivatives was evaluated using Swiss-ADME. The parent molecule and derivatives were then docked into the binding pocket of related crystal structures (PDB ID: 4G1Q, 1IKW, 1KLM and 3MEC). Genetic Optimization for Ligand Docking (GOLD) Suite 5.2.2 software was used for docking and the results analyzed in the Discovery Studio Visualizer 4. A derivative was chosen for further analysis, if it passed drug-likeliness and the docked energy was more favorable than that of its parent molecule. Out of the fifty-seven derivatives, forty-eight failed in drug-likeness screening by Swiss-ADME or at the docking stage.

Results: The final results showed that the selected compounds had higher predicted binding affinities than their parent scaffolds in both wild-type and the mutants. Binding energy improvement was higher for the structures designed based on second-generation NNRTIs (etravirine and rilpivirine) than the first-generation NNRTIs (delavirdine and efavirenz). For example, while the docked energy for rilpivirine was -51 KJ/mol, it was improved for its derivatives RPV01 and RPV15 up to - 58.3 and -54.5 KJ/mol, respectively.

Conclusion: In this study, we have identified and proposed some novel molecules with improved binding capacity for HIV RT using a fragment-based approach.

简介： 低分子量抑制剂对人类免疫缺陷病毒 (HIV) 逆转录酶 (RT) 的抑制仍然是一个活跃的研究领域。在这里，获得并讨论了新型化合物与 HIV-1 RT 结合口袋（野生型以及 Y181C 和 K103N 突变体）的蛋白质-配体相互作用和可能的结合模式。

方法：采用基于分子片段的方法，使用 FDA 批准的药物设计新的化学衍生物，使用地拉韦定、依非韦伦、依曲韦林和利匹韦林作为支架。使用 Swiss-ADME 评估衍生物的药物相似性。然后将母体分子和衍生物对接到相关晶体结构（PDB ID：4G1Q、1IKW、1KLM 和 3MEC）的结合口袋中。配体对接的遗传优化 (GOLD) Suite 5.2.2 软件用于对接，并在 Discovery Studio Visualizer 4 中分析结果。选择一个衍生物进行进一步分析，如果它通过药物相似性并且对接的能量比它的母体分子。在 57 个衍生品中，有 48 个在 Swiss-ADME 的药物相似性筛选或对接阶段失败。

结果：最终结果表明，在野生型和突变体中，所选化合物具有比其亲本支架更高的预测结合亲和力。基于第二代 NNRTIs（依曲韦林和利匹韦林）设计的结构的结合能改进高于第一代 NNRTIs（地拉韦定和依非韦伦）。例如，虽然 rilpivirine 的对接能量为 -51 KJ/mol，但其衍生物 RPV01 和 RPV15 分别提高到 - 58.3 和 -54.5 KJ/mol。

结论：在这项研究中，我们使用基于片段的方法鉴定并提出了一些具有改进的 HIV RT 结合能力的新分子。