Heroven Christina, Georgi Victoria, Ganotra Gaurav K, Brennan Paul, Wolfreys Finn, Wade Rebecca C, Fernández-Montalván Amaury E, Chaikuad Apirat, Knapp Stefan
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.
Bayer AG, Drug Discovery, Pharmaceuticals, Lead Discovery Berlin, 13353, Berlin, Germany.
Angew Chem Int Ed Engl. 2018 Jun 11;57(24):7220-7224. doi: 10.1002/anie.201801666. Epub 2018 May 9.
Prolonged drug residence times may result in longer-lasting drug efficacy, improved pharmacodynamic properties, and "kinetic selectivity" over off-targets with high drug dissociation rates. However, few strategies have been elaborated to rationally modulate drug residence time and thereby to integrate this key property into the drug development process. Herein, we show that the interaction between a halogen moiety on an inhibitor and an aromatic residue in the target protein can significantly increase inhibitor residence time. By using the interaction of the serine/threonine kinase haspin with 5-iodotubercidin (5-iTU) derivatives as a model for an archetypal active-state (type I) kinase-inhibitor binding mode, we demonstrate that inhibitor residence times markedly increase with the size and polarizability of the halogen atom. The halogen-aromatic π interactions in the haspin-inhibitor complexes were characterized by means of kinetic, thermodynamic, and structural measurements along with binding-energy calculations.
延长药物驻留时间可能会导致更持久的药效、改善的药效学性质以及对具有高药物解离速率的脱靶靶点的“动力学选择性”。然而，很少有策略被详细阐述来合理调节药物驻留时间，从而将这一关键性质整合到药物开发过程中。在此，我们表明抑制剂上的卤素部分与靶蛋白中的芳香族残基之间的相互作用可显著增加抑制剂的驻留时间。通过使用丝氨酸/苏氨酸激酶哈斯平与5-碘杀结核菌素（5-iTU）衍生物的相互作用作为典型活性状态（I型）激酶-抑制剂结合模式的模型，我们证明抑制剂的驻留时间随着卤素原子的大小和极化率而显著增加。通过动力学、热力学和结构测量以及结合能计算对哈斯平-抑制剂复合物中的卤素-芳香族π相互作用进行了表征。
