Computer-Aided Design of Anti-HIV Drugs

项目摘要/摘要 该研究计划的目的是发现有效、安全、容易的抗艾滋病毒新药。 给药，而且作用很长。这种方法结合了最先进的分子设计技术， 合成有机化学、生物测定和结晶学结构测定 设计了与蛋白质靶标结合的分子。PI的研究计划强调基础 药物设计软件和方法学的发展，蛋白质配基的详细建模 结合和有机合成。PI的小组已经开发了计算工具来加快Lead优化 对于效力，同时注意到需要令人满意的药理特性。对于艾滋病毒的工作， 与耶鲁医学院科学家的合作提供了生物活性的测定 在体外，在人类T细胞中，在人源化的小鼠模型中，以及通过蛋白质的大分子结构 结晶学。 具体的焦点是发现HIV-1逆转录酶(HIV-RT)的抑制物，这是一种 高效抗逆转录病毒疗法(HAART)的组成部分。上一次的授权期见证了惊人的 我们开发HIV-RT的儿茶酚二醚系列非核苷抑制剂的进展。 已发现的化合物显示出显著的效力，没有细胞毒性，没有脱靶活性， 出色的药理特性，在人源化的HIV-1感染小鼠模型中的疗效。从我们的 广泛的结晶学和建模研究，对结合位置的透彻了解也导致了 开发首个HIV-RT共价抑制剂的重要新方向。我们最初的目标是 临床上有问题的Tyr181Cys RT变体和设计的CRTIs完全破坏了 抗药性突变体。酶为Cys181共价修饰提供了确凿证据 感染人T细胞的抑制动力学、质谱学、蛋白质结晶学和抗病毒活性 化验。CRTIs对Cys181也有选择性，其细胞毒性低于批准的 药物法韦伦兹和利培韦林。我们的化合物是靶向共价变构抑制剂的罕见例子， 具有增强的潜力，低剂量，低毒性，并延长作用时间。广泛性 针对HIV-1野生型和耐药型的CRTIs的发现、鉴定和发展 是下一个授权期的重点。CRTIs是一类新型的抗HIV药物，具有潜在的深远意义 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.