Enhanced Molecular Dynamics Methods to Investigate GPCR Ligand Binding

 描述(申请人提供)：作为迄今为止已知的最重要的药物靶点家族之一，G蛋白偶联受体(GPCRs)继续是旨在发现改进疗法的大量研究努力的主题。尽管最近GPCRs的几个高分辨率晶体结构的出现使得发现针对这些受体的新化合物的成功率更高，但对这些化合物的体内疗效的准确预测是合理发现改进治疗药物的真正需要。虽然结合亲和力，即药物与其受体处于平衡状态的结合强度，经常被用作体内疗效的合适替代品，但对市场上成功的药物的回顾评估表明，动力学数量，如那些调节药物靶标复合体寿命的动力学数量，对于预测药物在活体中的疗效和/或安全性，可能与结合亲和力一样重要，甚至更重要。这项应用的总体目标是描述一种有效的计算策略，该策略除了能够识别嵌入显式膜模型的完全灵活的受体中正确的受体结合位置和配体结合模式外，还能够预测与GPCR配体结合相关的准确的动力学数量。这一战略有望补充目前GPCR的合理药物设计方法，从而为临床药物开发确定更好的候选药物。

 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.