Computer-Aided Design of Anti-HIV Drugs

描述（由申请人提供）：该研究项目具有最先进的计算设计，有机合成，生物分析和晶体学，旨在提供具有惊人潜力的临床候选药物来对抗艾滋病毒/艾滋病。目标是：(1)发展改进的技术和对有效的基于结构的药物设计的理解；(2)应用该技术创造具有广谱效力和优异药理学特性的新型抗hiv药物。基于结构的药物设计（SBDD）的研究项目涵盖了基本的技术进步——力场的发展、模拟软件和增强的计算方法，以及针对蛋白质配体结合、分子结构预测和抑制剂开发的应用。目前正在研究这些问题，重点是开发用于优化先导化合物和设计选择性阻断艾滋病毒复制的新化学实体的计算技术。原子水平的计算机模拟用于定量预测蛋白质配体复合物的结构和结合能量。对于抑制剂的设计，先导物的生成是通过配体生长程序BOMB来实现的，先导物的优化是通过蒙特卡罗（MC）统计力学的自由能摄动（FEP）计算来指导的。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变体具有高效能，并且具有良好的预测药理学特性。为了将活性谱扩展到更广泛的临床重要变异，目前正在寻求三种主要模板的新设计，即U- bihet - nh - ph， U- 5het - nh - ph和U- Het1-L-Het2，其中U是不饱和疏水性基团，Het是杂环，L是连接链。前两个基序定向NNRTI结合位点的U基团，这种方式在产生具有优异抗性谱的抑制剂方面是有先例的。最后一个基序专门针对Arnold的2be2晶体结构，该结构具有Tyr181的非典型取向，可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，以验证结合潜力和维持良好药理学特性的设计。设计、合成、分析和晶体学的强大结合的首要目标是为抗击艾滋病毒/艾滋病提供最好的临床候选药物。

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.