COMPUTER-AIDED DESIGN OF ANTIHIV DRUGS

描述：（改编自申请人摘要）将开发并应用计算方法来设计有效的抗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蛋白的结构、能量学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（NNRTIs）的非核苷酸抑制剂的活性。MCPRO软件系统将与ops力场一起用于rt配体复合物的广泛研究。具体来说，(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扰动（FEP）和线性响应（LRSA）计算，以寻求计算出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)对奈韦拉平和MKC-442的抗性将通过模拟关键突变对复合物与rt的结合亲和力和结构的影响来检验。适当的热力学循环也需要模拟，以提供未配体突变蛋白的结构，这些结构尚未通过衍射实验表征。(3)这些结果将为nnrti的设计奠定基础，该nnrti可以击败赋予抗性的突变。奈韦拉平和MKC-442的修饰，特别是针对关键的Y181C突变，将通过FEP计算对类似物与天然和突变蛋白的结合进行测试。新的nnrti也将通过以组合方式对计算方法的新颖扩展来开发和优化。

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.