Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India.
Bioinformatics centre, National Institute of Immunology, New Delhi, India.
J Biomol Struct Dyn. 2024 Sep;42(14):7150-7159. doi: 10.1080/07391102.2023.2238079. Epub 2023 Jul 24.
Maturation inhibitors (MIs) efficiently block HIV-1 maturation by inhibiting the cleavage of the capsid protein and spacer peptide 1 (CA-SP1) leading to the production of immature and non-infectious virus particles. We have previously reported that second-generation MIs were more potent than bevirimat (BVM) against HIV-1 subtype C. In-silico studies on interaction of with BVM and their analogs have been limited to HIV-1 subtype B(5I4T) due to lack of an available 3D structure for HIV-1 subtype C virus. In our current study, we have developed a 3D model of HIV-1C Gag CA-SP1 region using protein homology modeling with HIV-1 subtype B(514T) as a template. The HIV-1 C homology model generated was extensively validated using several online tools and served as a template to perform molecular docking studies with eight well-characterized MIs. The docked complex of HIV-1C and all nine MIs was subjected to molecular dynamics simulation for 100 ns using AMBER and binding free energy calculations were done using MM-GBSA. Based on our data, CV8611 exhibited highest binding energy of -6.5 Kcal/mol among all BVM analogs. CV8611 formed strong interactions with Gly222 and Met235 of HIV-1C Gag CA-SP1 during MD simulation and remained intact. The root mean square deviation and root mean square fluctuation values of the complex were stable during the simulations. Our study is the first to report construction and validation of 3D model for the HIV-1C Gag CA-SP1, which could serve as a crucial tool in the structure-aided design of novel and broadly acting maturation inhibitors.Communicated by Ramaswamy H. Sarma.
成熟抑制剂（MIs）通过抑制衣壳蛋白和间隔肽 1（CA-SP1）的切割，有效地阻止 HIV-1 的成熟，导致产生不成熟和无感染性的病毒颗粒。我们之前报道过第二代 MIs 对 HIV-1 亚型 C 的抑制作用比 bevirimat（BVM）更强。由于缺乏 HIV-1 亚型 C 病毒的可用 3D 结构，因此针对 BVM 及其类似物与 HIV-1 相互作用的计算机模拟研究仅限于 HIV-1 亚型 B（5I4T）。在我们目前的研究中，我们使用 HIV-1 亚型 B（514T）作为模板，通过蛋白质同源建模开发了 HIV-1C Gag CA-SP1 区域的 3D 模型。使用几种在线工具对生成的 HIV-1C 同源模型进行了广泛验证，并用作模板，对 8 种经过充分表征的 MIs 进行分子对接研究。将 HIV-1C 和所有 9 种 MIs 的对接复合物进行了 100ns 的分子动力学模拟，使用 AMBER 进行了结合自由能计算，并使用 MM-GBSA 进行了计算。根据我们的数据，CV8611 是所有 BVM 类似物中表现出最高结合能的 -6.5Kcal/mol。在 MD 模拟过程中，CV8611 与 HIV-1C Gag CA-SP1 的 Gly222 和 Met235 形成强烈相互作用，并保持完整。在模拟过程中，复合物的均方根偏差和均方根波动值保持稳定。我们的研究首次报道了 HIV-1C Gag CA-SP1 的 3D 模型的构建和验证，这可能成为新型和广泛作用的成熟抑制剂的结构辅助设计的重要工具。
