Enhanced Molecular Dynamics Methods to Investigate GPCR Ligand Binding

研究 GPCR 配体结合的增强分子动力学方法

• 批准号: 9044052
• 负责人: Marta Filizola
• 金额: $ 25.43万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9044052
• 关键词: Accounting; Adverse effects; Affinity; Binding; Binding Sites; Clinical Drug Development; Clinical Trials; Complement; Complex; Drug Design; Drug Kinetics; Drug Targeting; Drug Tolerance; Equilibrium; Family; G-Protein-Coupled Receptors; Goals; Kinetics; Lead; Ligand Binding; Marketing; Methods; Modeling; Organism; Pathway interactions; Patients; Pharmaceutical Preparations; Research; Resolution; Safety; Structure; Surrogate Markers; Therapeutic; Time; clinical application; clinical efficacy; design; drug candidate; drug efficacy; flexibility; improved; in vivo; insight; membrane model; molecular dynamics; novel; public health relevance; receptor; receptor binding; residence; success

 DESCRIPTION (provided by applicant): As one of the most important families of drug targets known to date, G protein coupled receptors (GPCRs) continue to be the subject of considerable research efforts directed towards discovering improved therapeutics. Although the recent availability of several high-resolution crystal structures of GPCRs enables a higher success rate in the discovery of novel compounds targeting these receptors, the accurate prediction of the in vivo efficacy of these compounds is what is really required for the rational discovery of improved therapeutics. Although binding affinity, i.e., the strength of association of a drug to its recepto at equilibrium, has often been used as an appropriate surrogate for in vivo efficacy, retrospective assessments of successful drugs in the market suggest that kinetic quantities, such as those that regulate the lifetime of the drug target complex, may be as important as, or even more important than, binding affinity for the prediction of the efficacy and/or safety of a drug in a liing organism. The overall goal of this application is to delineate an efficient computational strategy that is capable of predicting accurate kinetic quantities related to GPCR ligand binding in addition to identifying correct receptor binding sites and ligand binding modes in a completely flexible receptor embedded into an explicit membrane model. This strategy is expected to complement current rational drug design approaches for GPCRs, thus allowing the identification of better candidates for clinical drug development.

 描述（由适用提供）：作为迄今已知的最重要的药物靶标系列之一，G蛋白偶联受体（GPCR）仍然是针对发现改进治疗的研究工作的主题。尽管最近几种GPCR的几种高分辨率晶体结构的可用性在发现针对这些受体的新型化合物时可以取得更高的成功率，但是这些受体的准确预测这些受体的体内效率的准确预测尽管具有结合亲和力，但尽管具有相同的替代效率，但在其相等方面，该药物与其相关的相关性通常是在vivo效应中的相关性，该效率通常是在Vivi extiment中的概述，该效率是在Vivivo中的适当效应。数量，例如调节药物靶复合物的寿命的数量，可能比对预测谎言组织中药物的效率和/或安全性的结合亲和力同样重要，甚至更重要。该应用的总体目标是描述一种有效的计算策略，该策略能够预测与GPCR配体结合相关的准确动力学量，除了识别完全柔性受体中的正确受体结合位点和配体结合模式，并嵌入了明确的膜模型中。预计该策略将完成用于GPCR的当前合理药物设计方法，从而可以鉴定出更好的临床药物开发候选者。