{"title":"鉴定新型 HIV-1 整合酶链转移抑制剂：药效模型与体外试验相结合的协同方法","authors":"Sharif Karim Sayyed, Marzuqa Quraishi, Renitta Jobby, Neelamegam Rameshkumar, Tareeka Sonawane, Vinothkannan Ravichandran","doi":"10.1002/slct.202403809","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Background</h3>\n \n <p>AIDS is a highly prevalent and life-threatening global epidemic that severely compromises the host's immune system, increasing vulnerability to opportunistic diseases. The absence of definitive curative drugs emphasizes the importance and necessity of discovering novel anti-HIV agents.</p>\n </section>\n \n <section>\n \n <h3> Objective</h3>\n \n <p>This study aims to discover a natural molecular entity that acts as an Integrase strand transfer inhibitor (INSTI) with enhanced potency against HIV.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>A ligand-based pharmacophore model was developed for 4 FDA-approved INSTIs, with the potential for treating HIV-1. AutoDock facilitated molecular docking and free energy calculation to discern IN activity. Subsequently, MD simulations assessed interaction stability. ADMET analysis preceded an in vitro anti-HIV strand transfer assay.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>The generated model revealed a specific interaction involving Mg<sup>2+</sup> ion chelation. Crucial residues of HIV-1 IN and their respective free-binding energies were identified. The lead compound exhibited superior in silico characteristics which were substantiated by 100 ns MD simulations and MM-PBSA analysis. Additionally, the in vitro assay demonstrated potent inhibition with the lowest IC50, forming strong molecular interactions with IN.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>These findings showed valuable insights for the strategic development of new antiretroviral treatments (ART), paving the path for the development of natural therapeutic agents for HIV treatment.</p>\n </section>\n </div>","PeriodicalId":146,"journal":{"name":"ChemistrySelect","volume":"9 43","pages":""},"PeriodicalIF":1.9000,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Identification of a Novel HIV-1 Integrase Strand Transfer Inhibitor: A Synergistic Approach Combining Pharmacophore Modelling and In Vitro Assays\",\"authors\":\"Sharif Karim Sayyed, Marzuqa Quraishi, Renitta Jobby, Neelamegam Rameshkumar, Tareeka Sonawane, Vinothkannan Ravichandran\",\"doi\":\"10.1002/slct.202403809\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>AIDS is a highly prevalent and life-threatening global epidemic that severely compromises the host's immune system, increasing vulnerability to opportunistic diseases. 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引用次数: 0
摘要
背景 艾滋病是一种高度流行并威胁生命的全球性流行病，它严重损害宿主的免疫系统，增加了感染机会性疾病的可能性。由于缺乏确切的治疗药物，发现新型抗艾滋病病毒药物显得尤为重要和必要。 目的 本研究旨在发现一种天然分子实体，它可作为一种整合酶链转移抑制剂（INSTI），具有更强的抗 HIV 效力。 方法 为 4 种经 FDA 批准的 INSTIs 开发了基于配体的药理模型，这些 INSTIs 具有治疗 HIV-1 的潜力。通过 AutoDock 进行分子对接和自由能计算，以确定 IN 的活性。随后，MD 模拟评估了相互作用的稳定性。在体外抗 HIV 病毒链转移试验之前进行了 ADMET 分析。 结果 生成的模型揭示了一种涉及 Mg2+ 离子螯合的特异性相互作用。确定了 HIV-1 IN 的关键残基及其各自的自由结合能。先导化合物表现出卓越的硅学特性，100 ns MD 模拟和 MM-PBSA 分析证实了这一点。此外，体外试验显示，该化合物与 IN 形成了强烈的分子相互作用，具有最低的 IC50 抑制作用。 结论 这些发现为战略性开发新型抗逆转录病毒疗法（ART）提供了宝贵的启示，为开发治疗艾滋病的天然药物铺平了道路。
Identification of a Novel HIV-1 Integrase Strand Transfer Inhibitor: A Synergistic Approach Combining Pharmacophore Modelling and In Vitro Assays
Background
AIDS is a highly prevalent and life-threatening global epidemic that severely compromises the host's immune system, increasing vulnerability to opportunistic diseases. The absence of definitive curative drugs emphasizes the importance and necessity of discovering novel anti-HIV agents.
Objective
This study aims to discover a natural molecular entity that acts as an Integrase strand transfer inhibitor (INSTI) with enhanced potency against HIV.
Methods
A ligand-based pharmacophore model was developed for 4 FDA-approved INSTIs, with the potential for treating HIV-1. AutoDock facilitated molecular docking and free energy calculation to discern IN activity. Subsequently, MD simulations assessed interaction stability. ADMET analysis preceded an in vitro anti-HIV strand transfer assay.
Results
The generated model revealed a specific interaction involving Mg2+ ion chelation. Crucial residues of HIV-1 IN and their respective free-binding energies were identified. The lead compound exhibited superior in silico characteristics which were substantiated by 100 ns MD simulations and MM-PBSA analysis. Additionally, the in vitro assay demonstrated potent inhibition with the lowest IC50, forming strong molecular interactions with IN.
Conclusion
These findings showed valuable insights for the strategic development of new antiretroviral treatments (ART), paving the path for the development of natural therapeutic agents for HIV treatment.
期刊介绍：
ChemistrySelect is the latest journal from ChemPubSoc Europe and Wiley-VCH. It offers researchers a quality society-owned journal in which to publish their work in all areas of chemistry. Manuscripts are evaluated by active researchers to ensure they add meaningfully to the scientific literature, and those accepted are processed quickly to ensure rapid online publication.
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