Computer-Aided Design of Anti-HIV Drugs

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，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。这些进展包括计算工具的开发：（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）评估所提出的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库。计算方法的应用产生增强的知识的结构和能量的因素，支配蛋白质-配体结合亲和力的变化和蛋白质突变对药物活性的差异影响的起源。这些知识为合理设计药物提供了基础，这些药物对广泛的病毒突变体仍然有效。拟议的应用程序集中在改进的HIV-1逆转录酶（NNRTI）的非核苷抑制剂的开发进展。GenMol用于在蛋白质的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诱导的突变体的NNRTI。在蒙特卡罗（MC）模拟中加入溶剂和构型采样的额外细节允许更准确地表征活性变化。因此，MC/ELR（扩展线性响应）研究也进行了一系列的NNRTI与WT和突变体RT的目标是开发一个可靠的计算屏幕，以评估潜在的建议NNRTI。在最高计算水平，MC/FEP（自由能微扰）计算被用来阐明泛类耐药突变（如K103 N和Y188 L）对特定药物（包括奈韦拉平、依法韦仑、DPC 083和TMC 125）活性的差异效应的原子水平起源。随后，类似的研究将被用来设计有效的抑制剂，通过破坏gp 41-gp 120复合物的融合形式的组装，HIV病毒进入;特定的目标是一个疏水口袋，存在于由gp 41的N-末端片段形成的卷曲螺旋的脊中。

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.