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: 7161473
• 负责人: William L. Jorgensen
• 金额: $ 26.21万
• 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/7161473
• 关键词: Advanced Development; Affinity; Anti-HIV Agents; Binding; Binding Proteins; Binding Sites; Chemicals; Class; Complex; Computer Simulation; Computer-Aided Design; Computing Methodologies; DPC 083; Data; Development; Disruption; Drug Design; Free Energy; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1 Reverse Transcriptase; Individual; Knowledge; Lead; Libraries; Ligand Binding; Ligands; Mutation; N-terminal; Nevirapine; Pan Genus; Pharmaceutical Preparations; Play; Property; Protein Binding; Proteins; Range; Resistance; Role; Route; Sampling; Score; Series; Solvents; Statistical Mechanics; Structure; System; Technology; Variant; Viral; Virtual Library; Water; Work; analog; base; chemotherapy; combinatorial; computer studies; computerized tools; design; efavirenz; improved; inhibitor/antagonist; mutant; novel; nucleoside inhibitor; programs; protein structure; response; simulation

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.

这项工作的目的是开发、应用和传播计算技术， 先导化合物和设计新的化学实体，选择性地阻止艾滋病毒感染， 复制的这些进展包括：（a）预测蛋白质-配体结合的计算工具的开发 （B）评价蛋白质-配体复合物的性质和药物相似性， 提出的分子，和（c）创建和评估潜在抑制剂的虚拟库。的应用 通过计算方法，我们可以更深入地了解到， 蛋白质-配体结合亲和力的变化和蛋白质突变对细胞的不同影响的起源， 毒品活动。这一知识为合理设计药物提供了基础，这些药物仍然有效对抗 一系列的病毒突变体 所提出的应用集中于开发改进的非核苷类抗肿瘤药物的进展。 HIV-1逆转录酶（NNRTI）。GenMol用于构建单个有机分子或 蛋白质结合位点内的组合文库。开发必要的评分功能 需要应用于多个系列的野生型（WT）和所有主要的NNRTI诱导的 变种人在Monte Carlo（MC）中包含溶剂和构型采样的附加细节 模拟允许更准确地表征活性的变化。因此，MC/ELR（扩展线性 也对WT和突变RT的一系列NNRTI进行了研究，目的是 开发可靠的计算屏幕，以评估拟议的NNRTI的潜力。在最高 计算水平，MC/FEP（自由能微扰）计算被用来阐明原子- 泛类耐药突变如K103 N和Y188 L对耐药基因的差异效应的水平起源 特异性药物包括奈韦拉平、依法韦仑、DPC 083和TMC 125的活性。后来的，类似的 研究将用于设计通过破坏HIV病毒的组装来设计HIV病毒进入的有效抑制剂。 gp 41-gp 120复合物的融合形式;特异性靶标是存在于 由gp 41的N-末端片段形成的卷曲螺旋。