Computer-Aided Design of Anti-HIV Drugs

项目概要/摘要 该研究项目的目的是发现新的抗艾滋病毒药物，这些药物有效，安全，容易 给药，长效。该方法结合了最先进的分子设计技术， 合成有机化学，生物测定，和晶体结构的确定， 设计的分子与它们的蛋白质目标结合。PI的研究计划强调基础 药物设计软件和方法学的发展，蛋白质配体的详细建模 结合和有机合成。PI团队开发了计算工具来加速潜在客户优化 同时考虑到对所需药理学特性的需求。对于艾滋病工作， 与耶鲁大学医学院的科学家合作，提供了生物活性的测定， 体外、人T细胞和人源化小鼠模型中，以及通过蛋白质的大分子结构 结晶学 具体的重点是发现HIV-1逆转录酶（HIV-RT）抑制剂，这是一个核心问题。 高效抗逆转录病毒治疗（HAART）上一个赠款期见证了惊人的 为我们开发的儿茶酚二醚系列非核苷类HIV-RT抑制剂的进展。 已经发现化合物显示出显著的效力、无细胞毒性、无脱靶活性， 在HIV-1感染的人源化小鼠模型中具有优异的药理学性质和功效。从我们 广泛的晶体学和建模研究，结合位点的全面知识也导致了 这是开发第一个HIV-RT共价抑制剂（CRTIs）的重要新方向。我们最初的目标是 临床上有问题的Tyr 181 Cys RT变体和设计的CRTIs， 抗性突变体从酶的角度为Cys 181的共价修饰提供了确凿的证据 感染人T细胞中抑制动力学、质谱、蛋白质晶体学和抗病毒活性 测定。CRTIs也显示出对Cys 181的选择性，并且具有比批准的CRTIs更低的细胞毒性。 药物依法韦仑和利匹韦林。我们的化合物是靶向共价变构抑制剂的罕见实例， 其具有增强的低剂量、低毒性和延长的作用持续时间的潜力。广泛 发现、表征和开发靶向HIV-1野生型和耐药型的CRTIs 是下一个资助期的重点。CRTIs是一类新的抗HIV药物， 治疗效果

Project Summary/Abstract The purpose of the research program is to discover new anti-HIV drugs that are potent, safe, easily administered, and long-acting. The approach combines state-of-the-art technology for molecular design, synthetic organic chemistry, biological assaying, and crystallographic determination of structures of the designed molecules bound to their protein target. The PI's research program emphasizes fundamental advances in the development of software and methodology for drug design, detailed modeling of protein-ligand binding, and organic synthesis. The PI's group has developed computational tools to speed lead optimization for potency, while being mindful of the need for desirable pharmacological properties. For the HIV work, collaborations with scientist in the Yale School of Medicine provide the determinations of biological activity in vitro, in human T-cells, and in humanized mouse models, as well as macromolecular structures through protein crystallography. The specific focus is the discovery of inhibitors of HIV-1 reverse transcriptase (HIV-RT), which are a central component of highly active antiretroviral therapy (HAART). The previous grant period witnessed striking advances for our development of the catechol diether series of non-nucleoside inhibitors of HIV-RT. Compounds have been discovered that show remarkable potency, no cytotoxicity, no off-target activity, excellent pharmacological properties, and efficacy in a humanized mouse model of HIV-1 infection. From our extensive crystallographic and modeling studies, thorough knowledge of the binding site has also led to an important new direction of developing the first covalent inhibitors of HIV-RT (CRTIs). We initially targeted the clinically problematic Tyr181Cys RT variants and designed CRTIs that completely knock out activity of the resistant mutants. Conclusive evidence for the covalent modification of Cys181 is provided from enzyme inhibition kinetics, mass spectrometry, protein crystallography, and antiviral activity in infected human T-cell assays. The CRTIs were also shown to be selective for Cys181 and have lower cytotoxicity than the approved drugs efavirenz and rilpivirine. Our compounds are rare examples of targeted covalent allosteric inhibitors, which have enhanced potential for low dosage, low toxicity, and extended duration of action. Extensive discovery, characterization, and development of CRTIs targeting both wild type and resistant forms of HIV-1 are the focus for the next grant period. CRTIs are a new class of anti-HIV agents with potentially profound therapeutic impact.