La Sala Giuseppina, Pfleger Christopher, Käck Helena, Wissler Lisa, Nevin Philip, Böhm Kerstin, Janet Jon Paul, Schimpl Marianne, Stubbs Christopher J, De Vivo Marco, Tyrchan Christian, Hogner Anders, Gohlke Holger, Frolov Andrey I
Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca Gothenburg Sweden
Mathematisch-Naturwissenschaftliche Fakultät, Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf 40225 Düsseldorf Germany
Chem Sci. 2023 Jun 8;14(25):7057-7067. doi: 10.1039/d2sc06272k. eCollection 2023 Jun 28.
Understanding allosteric regulation in biomolecules is of great interest to pharmaceutical research and computational methods emerged during the last decades to characterize allosteric coupling. However, the prediction of allosteric sites in a protein structure remains a challenging task. Here, we integrate local binding site information, coevolutionary information, and information on dynamic allostery into a structure-based three-parameter model to identify potentially hidden allosteric sites in ensembles of protein structures with orthosteric ligands. When tested on five allosteric proteins (LFA-1, p38-α, GR, MAT2A, and BCKDK), the model successfully ranked all known allosteric pockets in the top three positions. Finally, we identified a novel druggable site in MAT2A confirmed by X-ray crystallography and SPR and a hitherto unknown druggable allosteric site in BCKDK validated by biochemical and X-ray crystallography analyses. Our model can be applied in drug discovery to identify allosteric pockets.
理解生物分子中的变构调节对药物研究具有重要意义，在过去几十年中出现了一些计算方法来表征变构偶联。然而，预测蛋白质结构中的变构位点仍然是一项具有挑战性的任务。在这里，我们将局部结合位点信息、共进化信息和动态变构信息整合到一个基于结构的三参数模型中，以识别具有正构配体的蛋白质结构集合中潜在隐藏的变构位点。当在五种变构蛋白（LFA-1、p38-α、GR、MAT2A和BCKDK）上进行测试时，该模型成功地将所有已知的变构口袋排在前三位。最后，我们通过X射线晶体学和表面等离子体共振（SPR）确定了MAT2A中的一个新的可成药位点，并通过生化和X射线晶体学分析验证了BCKDK中一个迄今未知的可成药变构位点。我们的模型可应用于药物发现以识别变构口袋。
