Computer Aided Drug Design and Molecular Modeling, Department of Bioinformatics, Alagappa University, Karaikudi, India.
J Cell Biochem. 2019 Jun;120(6):9063-9081. doi: 10.1002/jcb.28181. Epub 2018 Dec 3.
Protease inhibitors (PIs) are crucial drugs in highly active antiretroviral therapy for human immunodeficiency virus-1 (HIV-1) infections. However, resistance owing to mutations challenge the long-term efficacy in the medication of HIV-1-infected individuals. Lopinavir (LPV) and darunavir (DRV), two second-generation drugs are the most potent among PIs, hustling the drug resistance when mutations occur in the active and nonactive site of the protease (PR). Herein, we strive for compounds that can stifle the function of wild-type (WT) HIV-1 PR along with four major single mutants (I54M, V82T, I84V, and L90M) instigating resistance to the PIs using in silico approach. Six common compounds are retrieved from six databases using combined pharmacophore-based and structure-based virtual screening methodology. LPV and DRV are docked and the binding free energy is calculated to set the cut-off value for selecting compounds. Further, to gain insight into the stability of the complexes the molecular dynamics simulation (MDS) is carried out, which uncovers two lead molecules namely NCI-524545 and ZINC12866729. Both the lead molecules connect with WT and mutant HIV-1 PRs through strong and stable hydrogen bond interactions when compared with LPV and DRV throughout the trajectory analysis. Interestingly, NCI-524545 and ZINC12866729 exhibit direct interactions with I50/50' by replacing the conserved water molecule as evidenced by MDS, which indicates the credible potency of these compounds. Hence, we concluded that NCI-524545 and ZINC12866729 have great puissant to restrain the role of drug resistance HIV-1 PR variants, which can also show better activity through in vivo and in vitro conditions.
蛋白酶抑制剂（PIs）是治疗人类免疫缺陷病毒 1（HIV-1）感染的高效抗逆转录病毒治疗中的关键药物。然而，由于突变导致的耐药性挑战了 HIV-1 感染个体药物治疗的长期疗效。洛匹那韦（LPV）和达芦那韦（DRV）是第二代药物，是 PIs 中最有效的两种，当蛋白酶（PR）的活性和非活性部位发生突变时，会导致耐药性。在此，我们通过计算机模拟的方法，努力寻找能够抑制野生型（WT）HIV-1 PR 以及四个主要单突变体（I54M、V82T、I84V 和 L90M）功能的化合物，这些突变体导致对 PIs 的耐药性。使用基于药效团和基于结构的虚拟筛选方法，从六个数据库中检索到六种常见的化合物。对 LPV 和 DRV 进行对接，并计算结合自由能，以确定选择化合物的截止值。此外，为了深入了解复合物的稳定性，进行了分子动力学模拟（MDS），结果揭示了两种先导分子，即 NCI-524545 和 ZINC12866729。与 LPV 和 DRV 相比，这两种先导分子在整个轨迹分析过程中，通过与 WT 和突变 HIV-1 PR 形成强而稳定的氢键相互作用，与 WT 和突变 HIV-1 PR 连接。有趣的是，NCI-524545 和 ZINC12866729 通过取代保守的水分子与 I50/50' 直接相互作用，这一点在 MDS 中得到了证实，这表明这些化合物具有可信的效力。因此，我们得出结论，NCI-524545 和 ZINC12866729 具有强大的潜力，可以抑制耐药性 HIV-1 PR 变异体的作用，并且在体内和体外条件下可能显示出更好的活性。
