Computer-Aided Design of Anti-HIV Drugs

抗艾滋病毒药物的计算机辅助设计

• 批准号: 8588886
• 负责人: William L. Jorgensen
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588886
• 关键词: Address; Affinity; Anti-HIV Agents; Binding; Binding Proteins; Binding Sites; Biological; Biological Assay; Biological Availability; Catechols; Cells; Characteristics; Chemicals; Clinical; Clinical Trials; Collaborations; Complex; Computer Analysis; Computer Assisted; Computer software; Computer-Aided Design; Coupled; Development; Drug Design; Employee Strikes; Evaluation; Free Energy; Goals; Grant; Growth; HIV; HIV-1; Highly Active Antiretroviral Therapy; Human; Intellectual Property; Laboratories; Lead; Licensing; Link; Measurement; Metabolism; Methodology; Methods; Minor; Modeling; Modification; Molecular; Molecular Models; Molecular Structure; Organic Chemistry; Oxazoles; Performance; Permeability; Pharmaceutical Preparations; Positioning Attribute; Procedures; Property; Proteins; Pyrimidine; RNA-Directed DNA Polymerase; Reporting; Research; Safety; Series; Side; Signal Transduction; Solubility; Speed; Structure; T-Lymphocyte; Technology; Toxic effect; Triazines; Uracil; Variant; Viral; Virus; Work; analog; aqueous; base; computerized tools; design; improved; inhibitor/antagonist; innovation; molecular modeling; novel; nucleoside inhibitor; pre-clinical; programs; public health relevance; research study; screening; simulation; small molecule; software development; success

DESCRIPTION (provided by applicant): The purpose of the research program is to discover new anti-HIV drugs that are potent, safe, and easily administered. 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 spans fundamental advances in the development of software and methodology, detailed modeling of protein-ligand binding, inhibitor design, and small-molecule synthesis. Collaborations provide the determinations of biological activity in human T-cells and macromolecular structures. The PI's group has developed computational tools to speed lead optimization for potency, while being mindful of the need for desirable pharmacological properties. The specific focus is the discovery of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). NNRTIs are a central component of highly active antiretroviral therapy (HAART) in spite of significant deficiencies in the currently approved drugs in this class. The previous grant period witnessed striking advances for several chemical series including discovery of the most potent NNRTI ever reported for wild-type (WT) HIV-1. Means to enhance aqueous solubility, which has been problematic for most NNRTIs, also emerged. Building from these discoveries, new efforts are focused on advancing compounds from four chemical series into preclinical development. Catechol diethers are being further optimized to replace a cyanovinylphenyl group, which is a safety concern, with a substituted bicyclic heterocycle. In addition to the safety benefit, molecular modeling indicates that the new analogues should show enhanced anti-HIV activity. In addition, diarylamines and the catechol diethers are being modified with addition of a morpholinylalkoxy side chain that is strategically positioned to avoid significant reduction in potency, while providing a ca. 100-fold increase in aqueous solubility. Minor modifications of the solubilized diarylamines appear needed to yield preclinical candidates. Advances in a series containing an oxazole ring have also been made to provide excellent potency towards WT HIV-1 and the clinically important Tyr181Cys containing variant strain. In depth computational analysis led to a nearly 60- fold gain in potency towards the Tyr181Cys variant while retaining 5-nM potency towards the WT virus. Similar analyses are being carried out for the other prominent clinical variant, Lys103Asn; only a ca. 10-fold gain is needed to bring the potency towards strains with this replacement to the 10-nM level.

描述（由申请人提供）：该研究计划的目的是发现新的抗HIV药物，这些药物有效，安全，易于管理。该方法结合了分子设计、合成有机化学、生物测定和与蛋白质靶点结合的设计分子结构的晶体学测定的最新技术。PI的研究计划涵盖了软件和方法学开发的基本进展，蛋白质-配体结合的详细建模，抑制剂设计和小分子合成。合作提供人类T细胞和大分子结构的生物活性测定。PI的团队已经开发了计算工具来加速先导化合物的效力优化，同时注意到对理想药理学特性的需求。 具体重点是发现HIV-1逆转录酶的非核苷抑制剂（NNRTI）。尽管目前批准的药物存在显著缺陷，但非核苷类逆转录酶抑制剂是高效抗逆转录病毒治疗（HAART）的核心组成部分 在这门课上。上一个资助期见证了几个化学系列的惊人进展，包括发现了有史以来报道的针对野生型（WT）HIV-1的最有效的NNRTI。也出现了提高水溶性的方法，这对大多数NNRTI来说是个问题。在这些发现的基础上，新的努力集中在推进四个化学系列的化合物进入临床前开发。 邻苯二酚二醚正在进一步优化，以取代氰基乙烯基苯基，这是一个安全问题，与取代的双环杂环。除了安全性益处之外，分子建模表明新的类似物应该显示出增强的抗HIV活性。此外，二芳基胺和儿茶酚二醚通过添加吗啉基烷氧基侧链进行改性，所述吗啉基烷氧基侧链被策略性地定位以避免效力的显著降低，同时提供ca. 100-水溶性增加一倍。似乎需要对溶解的二芳基胺进行微小的修饰以产生临床前候选物。还在一系列含有恶唑环的药物中取得了进展，以提供针对WT HIV-1和临床上重要的含有Tyr 181 Cys的变异株的优异效力。深入的计算分析导致对Tyr 181 Cys变体的效力增加近60倍，同时保留对WT病毒的5 nM效力。类似的分析正在进行的其他突出的临床变异，Lys 103 Asn;只有一个ca。10-需要增加倍数以使对具有该替代物的菌株的效力达到10-nM水平。