Computer-Aided Design of Anti-HIV Drugs

这项工作的目的是开发、应用和传播计算机技术，以优化 先导化合物和设计新的化学实体，选择性地阻断艾滋病毒感染和 复制。这些进展包括开发计算工具(A)来预测蛋白质与配体的结合 蛋白质-配基复合体的亲和力和结构，(B)评价其性质和药物相似性 建议的分子，以及(C)创建和评估潜在抑制剂的虚拟文库。的应用。 计算方法产生了对支配结构和能量因素的增强知识 蛋白质-配体结合亲和力的变化以及蛋白质突变对 毒品活动。这一认识为合理设计仍然有效的药物提供了基础。 广泛的病毒突变体。 建议的应用重点是改进的非核苷抑制剂的开发进展。 HIV-1逆转录酶(NNRTI)。GenMol用于构建单个有机分子或 蛋白质结合部位内的组合库。发展必要的评分功能 需要应用于具有野生型(WT)和所有主要NNRTI诱导的多系列NNRTI 变种人。在蒙特卡罗(MC)中加入溶剂和构型取样所增加的细节 模拟可以更准确地描述活动性的变化。因此，MC/ELR(扩展线性 响应)还对具有WT和突变体RT的一系列NNRTI进行了研究，目标是 开发一种可靠的计算筛选，以评估拟议的NNRTIs的潜力。在最高 在计算水平上，MC/FEP(自由能微扰)计算被用来阐明原子-- K103N和Y188L等泛类耐药突变对人白血病细胞株差异效应的水平起源 特定药物的活性，包括奈韦拉平、Eefavirenz、DPC083和TMC125。随后，类似的 研究将用于通过破坏HIV病毒的组装来设计有效的HIV病毒进入抑制剂 融合形式的gp41-gp120复合体；特定的靶点是存在于 由gp41的N端段组成的盘绕线圈。

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.