Surade Sachin, Blundell Tom L
Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
Chem Biol. 2012 Jan 27;19(1):42-50. doi: 10.1016/j.chembiol.2011.12.013.
Over the past decade, researchers in the pharmaceutical industry and academia have made retrospective analyses of successful drug campaigns in order to establish "rules" to guide the selection of new target proteins. They have identified features that are considered undesirable and some that make targets "unligandable." This review focuses on the factors that make targets difficult: featureless binding sites, the lack of hydrogen-bond donors and acceptors, the presence of metal ions, the need for adaptive changes in conformation, and the lipophilicity of residues at the protein-ligand interface. Protein-protein interfaces of multiprotein assemblies share many of these undesirable features, although those that involve concerted binding and folding in their assembly have better defined pockets or grooves, and these can provide opportunities for identifying hits and for lead optimization. In some protein-protein interfaces conformational changes-often involving rearrangement of large side chains such as those of tyrosine, tryptophan, or arginine-are required to configure an appropriate binding site, and this may require tethering of the ligands until higher affinity is achieved. In many enzymes, larger conformational rearrangements are required to form the binding site, and these can make fragment-based approaches particularly difficult.
在过去十年中，制药行业和学术界的研究人员对成功的药物研发活动进行了回顾性分析，以建立“规则”来指导新靶蛋白的选择。他们确定了一些被认为不理想的特征，以及一些使靶点“不可成药”的特征。本综述重点关注使靶点难以成药的因素：无特征的结合位点、缺乏氢键供体和受体、存在金属离子、需要构象适应性变化以及蛋白质-配体界面处残基的亲脂性。多蛋白组装体的蛋白质-蛋白质界面具有许多这些不理想的特征，尽管那些在组装过程中涉及协同结合和折叠的界面具有更明确的口袋或凹槽，这些可以为识别活性分子和先导优化提供机会。在一些蛋白质-蛋白质界面中，需要构象变化——通常涉及酪氨酸、色氨酸或精氨酸等大侧链的重排——来构建合适的结合位点，这可能需要将配体连接起来，直到获得更高的亲和力。在许多酶中，需要更大的构象重排来形成结合位点，这会使基于片段的方法特别困难。
