Computer-Aided Design of Anti-HIV Drugs

描述（由申请人提供）：该工作的目的是开发、应用和传播用于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的计算技术。这些进展包括计算工具的发展(a)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)评估所提议分子的性质和药物相似性，以及(c)创建和评估潜在抑制剂的虚拟文库。计算方法的应用增强了对结构和能量因素的认识，这些因素控制着蛋白质与配体结合亲和力的变化，以及蛋白质突变对药物活性的不同影响的起源。这些知识为合理设计药物提供了基础，这些药物可以有效地对抗多种病毒突变体。提出的应用重点是开发改进的HIV-1逆转录酶（NNRTIs）的非核苷类抑制剂。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诱导突变体的nnrti。在蒙特卡罗（MC）模拟中加入溶剂和构型采样所增加的细节可以更准确地表征活性的变化。因此，MC/ELR（扩展线性响应）研究也对一系列具有WT和突变RT的nnrti进行了研究，目的是开发一个可靠的计算筛选来评估所提出的nnrti的潜力。在最高的计算水平上，MC/FEP（自由能摄动）计算被用于阐明泛类耐药突变（如K103N和Y188L）对奈韦拉平、依非韦伦、DPC083和TMC125等特定药物活性的差异效应的原子水平起源。随后，类似的研究将用于通过破坏gp41-gp120复合体的融合形式的组装来设计HIV病毒进入的有效抑制剂；特异性靶标是一个疏水袋，它存在于由gp41的n端片段形成的卷曲线圈的脊中。

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.