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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要