COMPUTER-AIDED DESIGN OF ANTIHIV DRUGS

抗艾滋病药物的计算机辅助设计

• 批准号: 6488729
• 负责人: William L. Jorgensen
• 金额: $ 12.77万
• 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 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6488729
• 关键词: antiAIDS agent; combinatorial chemistry; drug design /synthesis /production; drug resistance; molecular dynamics; nevirapine; reverse transcriptase inhibitors

DESCRIPTION: (Adapted from Applicant's Abstract) Computational methods will be developed and applied to design effective anti-HIV drugs. Monte Carlo (MC) statistical mechanics and Molecular dynamics (MD) simulations will be used to yield quantitative predictions on the structure, energetics, and ligand binding for HIV proteins. The current focus is on understanding and optimizing the activity of non-nucleotide inhibitors of HIV-1 reverse transcriptase (NNRTIs). The MCPRO software system will be used with the OPLS force fields in extensive studies of RT-ligand complexes. Specifically, (1) free-energy perturbations (FEP) and liner response (LRSA) calculations will be carried out for a series of 10-50 analogs of nevirapine and MKC-442 to seek correlations between the computed binding affinities and observed anti-HIV-1 activities. The calculations will be executed in parallel on a multiprocessor computer system. The unprecedentedly large database of results will elucidate the origins of binding variations for RT and also further refine and validate the methodology. (2) Resistance to nevirapine and MKC-442 will be examined through simulations of the effects of key mutations on the binding affinities and structures of the complexes with RT. The appropriate thermodynamic cycle also requires simulations that will provide structures of the unliganded mutant proteins, which have not yet been characterized by diffraction experiments. (3) These results will form a basis for the design of NNRTIs that can defeat the resistance-conferring mutations. Modifications of nevirapine and MKC-442 aimed particularly at the key Y181C mutation will be tested through FEP calculations on the binding of analogs to the native and mutant protein. New NNRTIs will also be developed and optimized through the novel extension of the computational approaches in a combinatorial manner.

描述：（改编自申请人的摘要）计算方法将被开发和应用于设计有效的抗艾滋病毒药物。蒙特卡罗（MC）统计力学和分子动力学（MD）模拟将被用来产生定量预测的结构，能量学和配体结合的HIV蛋白。目前的重点是了解和优化HIV-1逆转录酶（NNRTI）的非核苷酸抑制剂的活性。MCPRO软件系统将与OPLS力场一起用于RT-配体复合物的广泛研究。具体而言，（1）将对奈韦拉平和MKC-442的一系列10-50种类似物进行自由能扰动（FEP）和线性响应（LRSA）计算，以寻求计算的结合亲和力与观察到的抗HIV-1活性之间的相关性。计算将在多处理器计算机系统上并行执行。空前庞大的结果数据库将阐明RT结合变异的起源，并进一步完善和验证方法。(2)耐奈韦拉平和MKC-442将通过模拟的关键突变的影响，结合亲和力和结构的复合物与RT。适当的热力学循环也需要模拟，将提供unliganded突变蛋白质的结构，尚未通过衍射实验表征。(3)这些结果将为设计能够击败耐药突变的NNRTI奠定基础。将通过FEP计算类似物与天然和突变蛋白的结合，对奈韦拉平和MKC-442的修饰（特别针对关键Y181 C突变）进行检测。新的NNRTI也将开发和优化，通过新的计算方法的组合方式的扩展。