Caporuscio Fabiana, Rastelli Giulio
Department of Life Sciences, University of Modena & Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
Future Med Chem. 2016 Oct;8(15):1887-1897. doi: 10.4155/fmc-2016-0098. Epub 2016 Sep 15.
Structural plasticity is an intrinsic property of proteins that allows each gene product to accomplish its tasks in a strictly regulated manner at a precise time and cellular location. Moreover, protein motions allow protein-ligand and protein-protein recognition. The knowledge of the conformational ensemble that a drug target populates may be crucial for the design of small molecules that can differently modulate its function. X-ray crystallography and NMR have endlessly provided snapshots of protein states. However, experimental structure determination is not always straightforward. Therefore, attempts have been made to depict protein conformational landscapes through molecular dynamics and enhanced sampling methods. Here, we review how accounting for protein dynamics through in silico generated out-of-the-box protein conformations has started to impact on drug discovery.
结构可塑性是蛋白质的一种内在特性，它使每个基因产物能够在精确的时间和细胞位置以严格调控的方式完成其任务。此外，蛋白质运动允许蛋白质 - 配体和蛋白质 - 蛋白质识别。了解药物靶点所占据的构象集合对于设计能够不同方式调节其功能的小分子可能至关重要。X射线晶体学和核磁共振不断提供蛋白质状态的快照。然而，实验性结构测定并不总是简单直接的。因此，人们已尝试通过分子动力学和增强采样方法来描绘蛋白质构象景观。在这里，我们综述了通过计算机生成的新颖蛋白质构象来考虑蛋白质动力学如何开始对药物发现产生影响。
