Research Center of Plant and Microbial Biotechnologies, Biodiversity and Environment, Faculty of Sciences, Mohammed V University, Rabat, Morocco.
Virology Department, National Reference Laboratory for HIV, Institute National of Hygiene, Rabat, Morocco.
Int J Immunopathol Pharmacol. 2024 Jan-Dec;38:3946320241231465. doi: 10.1177/03946320241231465.
Antiretroviral therapy (ART) efficacy is jeopardized by the emergence of drug resistance mutations in HIV, compromising treatment effectiveness. This study aims to propose novel analogs of Effavirenz (EFV) as potential direct inhibitors of HIV reverse transcriptase, employing computer-aided drug design methodologies.
Three key approaches were applied: a mutational profile study, molecular dynamics simulations, and pharmacophore development. The impact of mutations on the stability, flexibility, function, and affinity of target proteins, especially those associated with NRTI, was assessed. Molecular dynamics analysis identified G190E as a mutation significantly altering protein properties, potentially leading to therapeutic failure. Comparative analysis revealed that among six first-line antiretroviral drugs, EFV exhibited notably low affinity with viral reverse transcriptase, further reduced by the G190E mutation. Subsequently, a search for EFV-similar inhibitors yielded 12 promising molecules based on their affinity, forming the basis for generating a pharmacophore model.
Mutational analysis pinpointed G190E as a crucial mutation impacting protein properties, potentially undermining therapeutic efficacy. EFV demonstrated diminished affinity with viral reverse transcriptase, exacerbated by the G190E mutation. The search for EFV analogs identified 12 high-affinity molecules, culminating in a pharmacophore model elucidating key structural features crucial for potent inhibition.
This study underscores the significance of EFV analogs as potential inhibitors of HIV reverse transcriptase. The findings highlight the impact of mutations on drug efficacy, particularly the detrimental effect of G190E. The generated pharmacophore model serves as a pivotal reference for future drug development efforts targeting HIV, providing essential structural insights for the design of potent inhibitors based on EFV analogs identified in vitro.
抗逆转录病毒疗法（ART）的疗效受到 HIV 耐药突变的威胁，从而降低了治疗效果。本研究旨在通过计算机辅助药物设计方法，提出新型依非韦伦（EFV）类似物作为 HIV 逆转录酶的潜在直接抑制剂。
应用三种关键方法：突变谱研究、分子动力学模拟和药效团开发。评估了突变对目标蛋白（特别是与 NRTI 相关的蛋白）稳定性、灵活性、功能和亲和力的影响。分子动力学分析确定 G190E 突变为显著改变蛋白质性质的突变，可能导致治疗失败。比较分析表明，在六种一线抗逆转录病毒药物中，EFV 与病毒逆转录酶的亲和力显著降低，G190E 突变进一步降低了其亲和力。随后，对 EFV 类似物的搜索得到了 12 种基于亲和力的有前途的分子，为生成药效团模型奠定了基础。
突变分析指出 G190E 突变为影响蛋白质性质的关键突变，可能破坏治疗效果。EFV 与病毒逆转录酶的亲和力降低，G190E 突变进一步加剧了这种情况。对 EFV 类似物的搜索确定了 12 种高亲和力分子，最终得出了一个药效团模型，阐明了对强效抑制至关重要的关键结构特征。
本研究强调了 EFV 类似物作为 HIV 逆转录酶潜在抑制剂的重要性。研究结果突出了突变对药物疗效的影响，特别是 G190E 突变的不利影响。生成的药效团模型为针对 HIV 的未来药物开发提供了重要的参考，为基于体外鉴定的 EFV 类似物设计强效抑制剂提供了必要的结构见解。
