COMPUTER-AIDED DESIGN OF ANTIHIV DRUGS

描述：(摘自申请者摘要)计算方法将被开发并应用于设计有效的抗HIV药物。蒙特卡罗(MC)统计力学和分子动力学(MD)模拟将用于对HIV蛋白质的结构、能量和配体结合进行定量预测。目前的重点是了解和优化HIV-1逆转录酶(NNRTI)的非核苷酸抑制物的活性。MCPRO软件系统将与OPLS力场一起用于RT-配体络合物的广泛研究。具体地说，(1)将对奈韦拉平和MKC-442的一系列10-50个类似物进行自由能微扰(FEP)和线性响应(LRSA)计算，以寻求计算的结合亲和力和观察到的抗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结合变异的来源，并进一步完善和验证方法学。(2)奈韦拉平和MKC-442对奈韦拉平和MKC-442的耐药性将通过模拟关键突变对与RT的结合亲和力和结构的影响来检验。适当的热力学循环还需要模拟提供未连接的突变蛋白质的结构，这些结构尚未通过衍射实验进行表征。(3)这些结果将为设计能够击败抗药性突变的NNRTIs奠定基础。奈韦拉平和MKC-442的修饰特别针对关键的Y181C突变，将通过FEP计算类似物与天然和突变蛋白的结合来进行测试。还将通过以组合方式对计算方法进行新的扩展来开发和优化新的NNRTI。

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.