As an important antiviral target, HIV-1 integrase plays a key role in the viral life cycle, and five integrase strand transfer inhibitors (INSTIs) have been approved for the treatment of HIV-1 infections so far. However, similar to other clinically used antiviral drugs, resistance-causing mutations have appeared, which have impaired the efficacy of INSTIs. In the current study, to identify novel integrase inhibitors, a set of molecular docking-based virtual screenings were performed, and indole-2-carboxylic acid was developed as a potent INSTI scaffold. Indole-2-carboxylic acid derivative 3 was proved to effectively inhibit the strand transfer of HIV-1 integrase, and binding conformation analysis showed that the indole core and C2 carboxyl group obviously chelated the two Mg2+ ions within the active site of integrase. Further structural optimizations on compound 3 provided the derivative 20a, which markedly increased the integrase inhibitory effect, with an IC50 value of 0.13 μM. Binding mode analysis revealed that the introduction of a long branch on C3 of the indole core improved the interaction with the hydrophobic cavity near the active site of integrase, indicating that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.

中文翻译：

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吲哚-2-羧酸衍生物作为新型 HIV-1 整合酶链转移抑制剂的发现

HIV-1整合酶作为重要的抗病毒靶点，在病毒生命周期中发挥着关键作用，目前已有五种整合酶链转移抑制剂（INSTI）被批准用于治疗HIV-1感染。然而，与临床上使用的其他抗病毒药物类似，出现了引起耐药性的突变，这损害了INSTI的疗效。在当前的研究中，为了鉴定新型整合酶抑制剂，进行了一系列基于分子对接的虚拟筛选，并开发了吲哚-2-羧酸作为有效的 INSTI 支架。吲哚-2-羧酸衍生物3被证明能有效抑制HIV-1整合酶的链转移，结合构象分析表明吲哚核心与C2羧基明显螯合整合酶活性位点内的两个Mg2+离子。化合物3进一步结构优化得到衍生物20a，其整合酶抑制效果显着增强，IC50值为0.13 μM。结合模式分析表明，在吲哚核心C3上引入长分支改善了与整合酶活性位点附近疏水空腔的相互作用，表明吲哚-2-羧酸是开发整合酶抑制剂的有前景的支架。