Computer-Aided Design of Anti-HIV Drugs

该研究项目以最先进的计算设计、有机合成、生物检测、 和结晶学，旨在提供具有抗击艾滋病毒/艾滋病的显著潜力的临床候选人。 其目的是(1)开发有效结构药物的改进技术和理解 设计和(2)应用该技术创造具有广谱效力和 优良的药理作用。基于结构的药物设计(SBDD)研究计划跨越 基本技术进步--在开发力场、模拟软件和增强 计算方法，并针对蛋白质-配体结合、分子结构 预测和抑制剂开发。开展这些专题的重点是发展 用于优化先导化合物和设计新化学实体的计算技术 选择性地阻止艾滋病毒复制。原子级的计算机模拟用于产生定量的 蛋白质-配体复合体的结构和结合能预测。对于抑制剂设计，领导 配基生长程序炸弹促进了生成，而铅的优化则由自由- 使用蒙特卡罗(MC)统计力学的能量微扰(FEP)计算。 NNRTI(非核苷类逆转录酶抑制剂)类的新型抗HIV药物是有效的 发现对WT HIV-1和K103N HIV-RT变异体具有高效力，并具有吉祥 预测的药理特性。将活动范围扩大到更广泛的临床重要疾病 在三种主要模板U-Bihet-NH-Ph、U-5Het-NH-Ph和U-Het-NH-Ph中，正在进行新的设计。 Het1-L-Het2，其中U为不饱和疏水基团，Het为杂环，L为连接链。 前两个基序在NNRTI结合部位以一种很好的先例方式定位U基团 产生抗药性良好的缓蚀剂。最后一个主题专门针对阿诺德的2Be2水晶 结构，其特征是具有非典型取向的Tyr181，促进了耐药性的避免 与这种残基的突变有关。大量的初步计算研究已经被 根据结合潜力和良好药理的维护来验证设计 属性。最重要的目标是将设计、合成、分析和 结晶学的努力是为抗击艾滋病毒/艾滋病提供可能的最佳临床候选者。

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 pharmacologica 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.