Discovery and use of chemical probes through SuFEx chemistry, computational design and predictive modeling

通过 SuFEx 化学、计算设计和预测建模发现和使用化学探针

• 批准号: 10242910
• 负责人: ARTHUR J. OLSON
• 金额: $ 28.33万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242910
• 关键词: Affinity; Allosteric Site; Automobile Driving; Base Sequence; Binding; Binding Sites; Biochemical; Biological Assay; Biology; Chemicals; Chemistry; Collaborations; Communities; Complement; Complex; Computing Methodologies; Data; Development; Discipline; Docking; Drug Design; Drug Targeting; Drug resistance; Evolution; Fluorine; Free Energy; HIV; HIV Integrase Inhibitors; HIV-1; HIV-1 integrase; Human; Integrase; Integrase Inhibitors; Label; Laboratories; Lead; Libraries; Life Cycle Stages; Ligands; Methodology; Methods; Microscopy; Modeling; Molecular Probes; Nucleic Acids; Patients; Play; Property; Proteins; Protocols documentation; Reaction; Reagent; Research Personnel; Resolution; Retinol Binding Proteins; Role; Site; Structure; Sulfur; System; Testing; Therapeutic; Validation; Viola; Viral; Viral Proteins; Virion; Virus Assembly; Work; design; diverse data; experimental study; improved; inhibitor/antagonist; innovation; interest; macromolecule; molecular scale; multidrug resistance inhibition therapy; novel; novel therapeutics; predictive modeling; success; viral resistance; virtual screening

ABSTRACT Chemical biology is playing an increasing role in helping to discover and elucidate the structural and mechanistic aspects of complex biomolecular systems. Project 6 will develop chemical probes for use in functional analysis and fluorescent labeling of critical structures and assemblies in the HIV life cycle, as well as design new modes of inhibition in drug resistant targets. The project will take a multipronged approach, built around the highly innovative Sulfur (VI) Fluorine Exchange (SuFEx) chemistry for discovering and designing reactive yet bioorthogonal specific molecules to selectively target macromolecules involved in the viral life cycle. SuFEx chemistry has shown great success in discovery of new binding modes to a wide variety of targets. Computational methods will complement this chemistry: ultrahigh-throughput virtual screening with reactive docking will add rational design to the method, and mesoscale modeling will integrate diverse data from the HIV structural community into models of viral and host protein assemblies. The project involves close collaborations with other HIVE investigators who will provide experimental assays and verification of the methods, hypotheses, and reagents that are developed. The combination of chemistry and computation will complement and extend the structural and functional data gathered by experiments proposed in other projects, serving the following specific aims: 1) Design and create diversity oriented rational SuFEx moiety-containing library of irreversible binding probes for activity/function modulation of HIV targets; 2) Virtual screening, reactive docking and free energy perturbation calculations for modulation of protein- protein and protein-nucleic acid interactions of viral and host macromolecules; 3) Modeling, structure- and evolutionary sequence-based rational design of new allosteric HIV Integrase inhibitors; 4) Development of mesoscale integrative HIV modeling for inhibitor and drug target discovery. The project will design novel computational protocols to generate and test new hypotheses by integrating the large amount of structural and biochemical data generated in other HIVE Projects. These models will provide rational support driving the design of new molecular probes, and lead to new drug design methodologies and therapeutic advances to treat HIV infected patients who have developed drug resistance to standard therapies. The SuFEx chemistry effort will be led by Sharpless, and the computational work will involve Olson, Goodsell and Levy, with outside collaborators Viola, and Wade. Experimental assays and hypothesis validation will involve the laboratories of HIVE investigators Torbett, Kvaratskhelia, Sarafianos, Arnold, Musier-Forsyth, Lyumkis, Millar, Williamson, Marcotrigiano and Griffin.

抽象的 化学生物学在帮助发现和阐明结构和 复杂生物分子系统的机械方面。项目6将开发用于使用的化学探针 HIV生命周期中关键结构和组件的功能分析和荧光标记以及 设计耐药靶标的新抑制模式。该项目将采用多收益的方法 在高度创新的硫（VI）氟交换（Sufex）化学围绕发现和设计 反应性但生物正交的特异性分子，以选择性地靶向参与病毒寿命的大分子 循环。 Sufex化学在发现新的绑定模式方面取得了巨大的成功 目标。计算方法将补充这种化学：超高通量虚拟筛选 反应式对接将为该方法增加合理的设计，并且中尺度建模将整合多种数据 从HIV结构群落到病毒和宿主蛋白质组件的模型。该项目涉及关闭 与其他将提供实验测定和验证的蜂巢调查人员的合作 开发的方法，假设和试剂。化学和计算的结合将 补充并扩展了其他项目中提出的实验收集的结构和功能数据， 服务以下特定目标： 1）设计和创建以多样性为导向的有理sufex部分不可逆的结合探针库 用于HIV目标的活动/功能调制； 2）虚拟筛查，反应性对接和自由能扰动计算，以调节蛋白质 病毒和宿主大分子的蛋白质和蛋白质核酸相互作用； 3）基于建模，结构和进化序列的新变构艾滋病毒整合酶的合理设计 抑制剂； 4）开发用于抑制剂和药物靶标发现的中尺度综合HIV建模。 该项目将设计新颖的计算协议，以通过集成 其他蜂巢项目中产生的大量结构和生化数据。这些模型将提供 理性支持推动新分子探针的设计，并导致新的药物设计方法和 治疗对艾滋病毒感染的患者的治疗进展，这些患者对标准疗法产生了耐药性。 Sufex化学工作将由Sharpless领导，计算工作将涉及Olson，Goodsell 和Levy，外部合作者中提琴和韦德。实验测定和假设验证将 参与蜂巢调查人员的实验室托尔贝特（Torbett Lyumkis，Millar，Williamson，Marcotrigiano和Griffin。