Department of Biochemistry, Rosenstiel Basic Medical Sciences Center, Brandeis University, 415 South Street MS 029, Waltham, MA 02454, USA.
J Comput Aided Mol Des. 2009 Aug;23(8):491-500. doi: 10.1007/s10822-009-9283-2. Epub 2009 Jun 12.
The identification of hot spots, i.e., binding regions that contribute substantially to the free energy of ligand binding, is a critical step for structure-based drug design. Here we present the application of two fragment-based methods to the detection of hot spots for DJ-1 and glucocerebrosidase (GCase), targets for the development of therapeutics for Parkinson's and Gaucher's diseases, respectively. While the structures of these two proteins are known, binding information is lacking. In this study we employ the experimental multiple solvent crystal structures (MSCS) method and computational fragment mapping (FTMap) to identify regions suitable for the development of pharmacological chaperones for DJ-1 and GCase. Comparison of data derived via MSCS and FTMap also shows that FTMap, a computational method for the identification of fragment binding hot spots, is an accurate and robust alternative to the performance of expensive and difficult crystallographic experiments.
热点的识别，即对配体结合自由能有显著贡献的结合区域，是基于结构的药物设计的关键步骤。在这里，我们介绍了两种基于片段的方法在 DJ-1 和葡萄糖脑苷脂酶（GCase）热点检测中的应用，DJ-1 和 GCase 分别是开发治疗帕金森病和戈谢病药物的靶点。虽然这两种蛋白质的结构是已知的，但缺乏结合信息。在这项研究中，我们采用实验多溶剂晶体结构（MSCS）方法和计算片段映射（FTMap）来确定适合开发 DJ-1 和 GCase 药理学伴侣的区域。通过 MSCS 和 FTMap 获得的数据的比较也表明，FTMap 是一种用于识别片段结合热点的计算方法，是进行昂贵且困难的晶体学实验的准确且稳健的替代方法。
