Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, People's Republic of China.
Mol Divers. 2019 Feb;23(1):107-121. doi: 10.1007/s11030-018-9860-1. Epub 2018 Jul 26.
Diarylpyrimidines (DAPYs), a type of effective HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), have been considered as one of the most successful agents for treating AIDS. A number of structurally diverse DAPYs have been designed and synthesized in the past decade, and most of them exhibited potent anti-HIV-1 activities; however, the structure-activity relationships of recently reported DAPYs and their pharmacophore features that interacted with HIV-1 reverse transcriptase (RT) remain to be studied. In the present study, molecular docking studies were first performed on three novel classes of DAPYs to study their binding pattern in the HIV-1 RT. Based on the docking conformations of these DAPYs, 3D-QSAR models were constructed using CoMSIA and Topomer CoMFA methods, and pharmacophore models were also built using distance comparison technique. All selected DAPYs presented preferred U- or L-shaped conformations while being docked into the non-nucleoside inhibitor-binding pocket of the HIV-1 RT. The best CoMSIA model exhibited powerful predictivity, with satisfactory statistical parameters such as a q of 0.572, an r of 0.952, and an [Formula: see text] of 0.728. Contour maps of the best CoMSIA model were in accordance with those of the Topomer CoMFA model, giving the insight into the feature requirements of DAPYs for the anti-HIV-1 activity. Three potential pharmacophore models were constructed, and each of them was consisted of five hypothesis features. All results suggested that the aromatic ring on the left wing of DAPYs and the central pyrimidine ring contained key pharmacophore features for the anti-HIV-1 activity, and also indicated that the right wing of DAPYs had potential for further structural modification to improve activity. Eight novel DAPY molecules with potential anti-HIV-1 activities were designed on the basis of the obtained results. The findings in this study might provide important information for further design and development of novel HIV-1 NNRTIs.
二芳基嘧啶（DAPY）是一种有效的 HIV-1 非核苷类逆转录酶抑制剂（NNRTI），被认为是治疗艾滋病最成功的药物之一。在过去的十年中，设计和合成了许多结构不同的 DAPY，其中大多数具有很强的抗 HIV-1 活性；然而，最近报道的 DAPY 的构效关系及其与 HIV-1 逆转录酶（RT）相互作用的药效团特征仍有待研究。在本研究中，首先对三类新型 DAPY 进行了分子对接研究，以研究它们在 HIV-1 RT 中的结合模式。基于这些 DAPY 的对接构象，使用 CoMSIA 和 Topomer CoMFA 方法构建了 3D-QSAR 模型，并使用距离比较技术构建了药效团模型。所有选定的 DAPY 在对接 HIV-1 RT 的非核苷抑制剂结合口袋时，均呈现出首选的 U 形或 L 形构象。最佳的 CoMSIA 模型具有强大的预测能力，具有令人满意的统计参数，如 q 值为 0.572、r 值为 0.952 和[Formula: see text]值为 0.728。最佳 CoMSIA 模型的轮廓图与 Topomer CoMFA 模型一致，为 DAPY 对抗 HIV-1 活性的特征要求提供了深入的了解。构建了三个潜在的药效团模型，每个模型都由五个假设特征组成。所有结果表明，DAPY 左翅上的芳环和中心嘧啶环包含抗 HIV-1 活性的关键药效团特征，也表明 DAPY 的右翅具有进一步结构修饰以提高活性的潜力。基于获得的结果设计了 8 种具有潜在抗 HIV-1 活性的新型 DAPY 分子。本研究的结果可能为进一步设计和开发新型 HIV-1 NNRTI 提供重要信息。
