目的:抗逆转录病毒治疗(ART)的疗效因HIV耐药突变的出现而受到损害,影响治疗效果。本研究旨在提出Effavirenz(EFV)的新型类似物作为HIV逆转录酶的潜在直接抑制剂,采用计算机辅助药物设计方法。
方法:应用了三种关键方法:突变谱研究,分子动力学模拟,和药效团的发展。突变对稳定性的影响,灵活性,函数,和靶蛋白的亲和力,尤其是那些与NRTI有关的,被评估。分子动力学分析确定G190E是一种显著改变蛋白质性质的突变,可能导致治疗失败。比较分析显示,在六种一线抗逆转录病毒药物中,EFV与病毒逆转录酶表现出明显的低亲和力,进一步减少G190E突变。随后,对EFV相似抑制剂的搜索基于其亲和力产生了12个有前途的分子,形成生成药效团模型的基础。
结果:突变分析指出G190E是影响蛋白质特性的关键突变,可能会破坏治疗效果。EFV显示与病毒逆转录酶的亲和力降低,G190E突变加剧了.对EFV类似物的搜索确定了12个高亲和力分子,最终形成药效团模型,阐明对有效抑制至关重要的关键结构特征。
结论: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。研究结果强调了突变对药物疗效的影响,特别是G190E的不利影响。生成的药效团模型作为未来针对HIV的药物开发工作的关键参考。为基于体外鉴定的EFV类似物的有效抑制剂的设计提供必要的结构见解。
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.