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: 8207296
• 负责人: William L. Jorgensen
• 金额: $ 32.44万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207296
• 关键词: AIDS/HIV problem; Affinity; Anti-HIV Agents; Area; Automation; Binding; Binding Proteins; Binding Sites; Biological Assay; Biological Availability; Characteristics; Chemicals; Clinical; Complex; Computer Simulation; Computer-Aided Design; Computing Methodologies; Coupled; Crystallography; Development; Drug Design; Drug resistance; Employee Strikes; Free Energy; Generations; Goals; Grant; HIV; HIV-1; Lead; Libraries; Ligands; Link; Maintenance; Molecular; Molecular Models; Molecular Structure; Mutation; Organic Synthesis; Pharmaceutical Preparations; Property; Proteins; RNA-Directed DNA Polymerase; Research; Resistance profile; Route; Statistical Mechanics; Structure; T-Lymphocyte; Technology; Therapeutic; Toxic effect; Variant; Viral; Water; Work; base; combat; combinatorial; computer studies; design; direct application; improved; inhibitor/antagonist; model design; molecular modeling; non-nucleoside reverse transcriptase inhibitors; novel; programs; simulation; simulation software; software systems; success

The research program features state-of-the-art computational design, organic synthesis, biological assaying, and crystallography aimed at delivering clinical candidates with striking potential for combating HIV/AIDS. The aims are to (1) develop improved technology and understanding for efficient structure-based drug design and (2) apply the technology to create new anti-HIV agents with broad-spectrum potency and excellent pharmacological properties. The research program on structure-based drug design (SBDD) spans fundamental technical advances- in the development of force fields, software for simulations, and enhanced computational methodology, and features applications directed at protein-ligand binding, molecular structure prediction, and inhibitor development. These topics are being pursued with emphasis on development of computational technology for the optimization of lead compounds and for the design of new chemical entities that selectively block HIV replication. Atomic-level computer simulations are used to yield quantitative predictions for the structures and binding energetics of protein-ligand complexes. For inhibitor design, lead generation is facilitated with the ligand-growing program BOMB, and lead optimization is guided by free- energy perturbation (FEP) calculations using Monte Carlo (MC) statistical mechanics. Novel anti-HIV agents in the NNRTI (non-nucleoside reverse transcriptase inhibitors) class were efficiently discovered with high potency towards WT HIV-1 and the K103N HIV-RT variant and with auspicious predicted pharmacological properties. To expand the activity spectrum to a wider range of clinically important variants, new designs are being pursued in three principal templates, U-biHet-NH-Ph, U-5Het-NH-Ph, and U- Het1-L-Het2, where U is an unsaturated hydrophobic group, Het is a heterocycle, and L is a linking chain. The first two motifs orient the U group in the NNRTI binding site in a manner that is well precedented for yielding inhibitors with excellent resistance profiles. The last motif specifically targets Arnold's 2be2 crystal structure, which features an atypical orientation of Tyr181 that promotes avoidance of drug resistance associated with mutations of this residue. Substantial preliminary computational studies have been performed to validate the designs in terms of binding potential and maintenance of good pharmacologica properties. The overriding goal of the powerful combination of design, synthesis, assaying, and crystallography efforts is to deliver the best possible clinical candidates for combating HIV/AIDS.

该研究项目以最先进的计算设计、有机合成、生物分析、 和晶体学旨在提供具有抗击艾滋病毒/艾滋病巨大潜力的临床候选药物。 目标是 (1) 开发改进的技术和对高效基于结构的药物的理解 设计并 (2) 应用该技术来创造具有广谱效力的新型抗 HIV 药物， 优良的药理特性。基于结构的药物设计（SBDD）研究计划涵盖 基础技术进步——力场、模拟软件的开发以及增强 计算方法，以及针对蛋白质-配体结合、分子结构的应用程序 预测和抑制剂开发。正在研究这些主题，重点是发展 用于优化先导化合物和设计新化学实体的计算技术 选择性地阻止 HIV 复制。原子级计算机模拟用于产生定量结果 蛋白质-配体复合物的结构和结合能量的预测。对于抑制剂设计，铅 配体生长程序 BOMB 促进了生成，并且先导化合物优化由自由引导 使用蒙特卡罗 (MC) 统计力学进行能量扰动 (FEP) 计算。 NNRTI（非核苷逆转录酶抑制剂）类新型抗 HIV 药物被有效地 发现对 WT HIV-1 和 K103N HIV-RT 变体具有高效力，并具有吉祥意义 预测的药理特性。将活动范围扩大到更广泛的临床重要领域 变体，新的设计正在三个主要模板中进行，U-biHet-NH-Ph、U-5Het-NH-Ph 和 U- Het1-L-Het2，其中U是不饱和疏水基团，Het是杂环，L是连接链。 前两个基序以 NNRTI 结合位点中的 U 基团定向，其方式在 产生具有优异耐药性的抑制剂。最后一个图案专门针对阿诺德的 2be2 水晶 结构，其特点是 Tyr181 的非典型方向，可促进避免耐药性 与该残基的突变有关。大量的初步计算研究已经完成 进行以验证设计的结合潜力和良好药理学的维持 特性。设计、合成、分析和分析的强大结合的首要目标 晶体学的努力是为了提供抗击艾滋病毒/艾滋病的最佳临床候选药物。