Computer-Aided Design of Anti-HIV Drugs

描述(由申请者提供)：该研究项目以最先进的计算设计、有机合成、生物分析和结晶学为特色，旨在为临床候选人提供抗击艾滋病毒/艾滋病的显著潜力。其目的是(1)为有效的基于结构的药物设计开发改进的技术和理解，以及(2)应用该技术创造具有广谱效力和良好药理特性的新的抗艾滋病毒药物。基于结构的药物设计(SBDD)的研究计划跨越了基本的技术进步-在力场开发、模拟软件和增强的计算方法方面，并以针对蛋白质-配体结合、分子结构预测和抑制剂开发的应用为特色。这些专题的重点是开发计算技术，以优化先导化合物和设计有选择地阻止艾滋病毒复制的新化学实体。原子级计算机模拟用于对蛋白质-配体复合体的结构和结合能进行定量预测。对于缓蚀剂的设计，铅的生成通过配体生长程序Bomb来促进，铅的优化是通过使用蒙特卡罗(MC)统计力学的自由能微扰(FEP)计算来指导的。NNRTI(非核苷类逆转录酶抑制剂)类新的抗HIV药物被有效地发现，对WT HIV-1和K103N HIV-RT变异体具有高效力，并具有良好的药理作用。为了将活性谱扩展到更广泛的临床重要变体，正在进行三个主要模板的新设计，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。前两个基序以一种在NNRTI结合位点上定位U基团的方式定位，这在产生具有良好耐药性曲线的抑制剂方面是很好的先例。最后一个基序专门针对Arnold的2be2晶体结构，该晶体结构具有Tyr181的非典型取向，促进避免与该残基突变相关的耐药性。已经进行了大量的初步计算研究，以验证设计在结合潜力和保持良好的药理学特性方面的有效性。设计、合成、分析和结晶学努力的强大组合的压倒一切的目标是为抗击艾滋病毒/艾滋病提供可能的最佳临床候选药物。

DESCRIPTION (provided by applicant): 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 pharmacological 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.