Computer-Aided Design of Anti-HIV Drugs

抗艾滋病毒药物的计算机辅助设计

• 批准号: 6777086
• 负责人: William L. Jorgensen
• 金额: $ 27.76万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6777086
• 关键词: Computer; Aided; Design; Anti; HIV

DESCRIPTION (provided by applicant): The aim of the work is to develop, apply, and disseminate computational technology for the optimization of lead compounds and for the design of new chemical entities that selectively block HIV infection and replication. The advances include development of computational tools (a) to predict protein-ligand binding affinities and the structures of protein-ligand complexes, (b) to evaluate properties and drug-likeness of proposed molecules, and (c) to create and evaluate virtual libraries of potential inhibitors. Applications of the computational methods yield enhanced knowledge of the structural and energetic factors that govern variations in protein-ligand binding affinities and of the origins of differential effects of protein mutations on drug activities. This knowledge provides a basis for the rational design of drugs that remain effective against a broad range of viral mutants. The proposed applications focus on advances for the development of improved non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). GenMol is used to construct individual organic molecules or combinatorial libraries inside a protein's binding site. Development of the necessary scoring functions requires application to multiple series of NNRTIs with wild type (WT) and all principal NNRTI-induced mutants. The added detail from inclusion of the solvent and configurational sampling in Monte Carlo (MC) simulations permits more accurate characterization of variations in activity. Thus, MC/ELR (extended linear response) studies are also performed for series of NNRTIs with WT and mutant RT with the goal of developing a reliable computational screen to evaluate the potential of proposed NNRTIs. At the highest computational level, MC/FEP (free energy perturbation) calculations are being used to elucidate the atomic level origins of the differential effects of pan-class resistance mutations such as K103N and Y188L on the activity of specific drugs including nevirapine, efavirenz, DPC083, and TMC125. Subsequent, analogous studies will be used to design potent inhibitors of HIV viral entry through disruption of assembly of the fusogenic form of the gp41-gp120 complex; the specific target is a hydrophobic pocket that exists in ridges of a coiled coil formed by N-terminal segments of gp41.

描述（由申请人提供）：这项工作的目的是开发、应用和传播计算技术，以优化先导化合物和设计选择性阻断 HIV 感染和复制的新化学实体。这些进展包括开发计算工具（a）来预测蛋白质-配体结合亲和力和蛋白质-配体复合物的结构，（b）评估拟议分子的特性和药物相似性，以及（c）创建和评估潜在抑制剂的虚拟库。计算方法的应用增强了对控制蛋白质-配体结合亲和力变化的结构和能量因素以及蛋白质突变对药物活性差异影响的起源的了解。这些知识为合理设计对多种病毒突变体仍然有效的药物提供了基础。拟议的申请重点关注改进的 HIV-1 逆转录酶非核苷抑制剂 (NNRTI) 的开发进展。 GenMol 用于在蛋白质结合位点内构建单个有机分子或组合文库。开发必要的评分函数需要应用于多个系列的野生型 (WT) NNRTI 和所有主要 NNRTI 诱导突变体。蒙特卡罗 (MC) 模拟中包含溶剂和构型采样所增加的细节可以更准确地表征活性变化。因此，还对一系列具有 WT 和突变体 RT 的 NNRTI 进行了 MC/ELR（扩展线性响应）研究，目的是开发可靠的计算筛选来评估所提出的 NNRTI 的潜力。在最高计算水平上，MC/FEP（自由能微扰）计算被用来阐明泛类耐药突变（例如 K103N 和 Y188L）对奈韦拉平、依非韦伦、DPC083 和 TMC125 等特定药物活性差异影响的原子水平起源。随后，类似的研究将用于通过破坏 gp41-gp120 复合物融合形式的组装来设计 HIV 病毒进入的有效抑制剂；具体目标是存在于由 gp41 N 端片段形成的卷曲线圈的脊中的疏水口袋。