Enhanced Molecular Dynamics Methods to Investigate GPCR Ligand Binding

 描述（由申请人提供）：作为迄今为止已知的最重要的药物靶标家族之一，G蛋白偶联受体（GPCR）继续是大量研究工作的主题，旨在发现改进的治疗方法。尽管最近几种GPCR的高分辨率晶体结构的可用性使得靶向这些受体的新型化合物的发现具有更高的成功率，但是这些化合物的体内功效的准确预测是合理发现改进的治疗剂真正需要的。尽管结合亲和力，即，药物与其受体在平衡状态下的结合强度经常被用作体内功效的适当替代物，对市场上成功药物的回顾性评估表明，动力学量，例如调节药物靶向复合物寿命的动力学量，可能与药物靶向复合物一样重要，甚至更重要，结合亲和力用于预测药物在活生物体中的功效和/或安全性。本申请的总体目标是描绘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，此外还能够识别嵌入显式膜模型中的完全柔性受体中的正确受体结合位点和配体结合模式。该策略有望补充目前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.