Computer-Aided Design of Anti-HIV Drugs

描述（由申请人提供）：该研究计划具有最先进的计算设计，有机合成，生物测定和晶体学，旨在提供具有对抗艾滋病毒/艾滋病的惊人潜力的临床候选人。其目的是（1）开发改进的技术和理解，以有效的基于结构的药物设计和（2）应用该技术创造新的抗艾滋病毒药物具有广谱效力和优良的药理学特性。基于结构的药物设计（SBDD）的研究计划涵盖了基本的技术进步-力场，模拟软件和增强的计算方法的发展，并具有针对蛋白质-配体结合，分子结构预测和抑制剂开发的应用。这些课题的研究重点是开发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。对于抑制剂设计，用配体生长程序BOMB促进铅生成，并且通过使用蒙特卡罗（MC）统计力学的自由能微扰（FEP）计算来指导铅优化。NNRTI（非核苷逆转录酶抑制剂）类的新型抗HIV药物被有效发现，对WT HIV-1和K103 N HIV-RT变体具有高效力，并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体，正在三种主要模板中进行新的设计，U-biHet-NH-Ph、U-5 Het-NH-Ph和U-Het 1-L-Het 2，其中U是不饱和疏水基团，Het是杂环，L是连接链。前两个基序在NNRTI结合位点中定向U基团，其方式对于产生具有优异抗性特征的抑制剂是有先例的。最后一个基序特异性靶向Arnold的2be 2晶体结构，其特征在于Tyr 181的非典型取向，其促进避免与该残基的突变相关的耐药性。已经进行了大量的初步计算研究，以验证结合潜力和良好的药理学性质的维持方面的设计。设计、合成、分析和晶体学工作的强大组合的首要目标是为抗击HIV/AIDS提供最佳的临床候选药物。

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.