Schnapp Gisela, Klein Thomas, Hoevels Yvette, Bakker Remko A, Nar Herbert
Department of Lead Identification and Optimization Support and ‡Department of CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach 88397, Germany.
J Med Chem. 2016 Aug 25;59(16):7466-77. doi: 10.1021/acs.jmedchem.6b00475. Epub 2016 Aug 4.
The binding kinetics and thermodynamics of dipeptidyl peptidase (DPP)-4 inhibitors (gliptins) were investigated using surface plasmon resonance and isothermal titration calorimetry. Binding of gliptins to DPP-4 is a rapid electrostatically driven process. Off-rates were generally slow partly because of reversible covalent bond formation by some gliptins, and partly because of strong and extensive interactions. Binding of all gliptins is enthalpy-dominated due to strong ionic interactions and strong solvent-shielded hydrogen bonds. Using a congeneric series of molecules which represented the intermediates in the lead optimization program of linagliptin, the onset of slow binding kinetics and development of the thermodynamic repertoire were analyzed in the context of incremental changes of the chemical structures. All compounds rapidly associated, and therefore the optimization of affinity and residence time is highly correlated. The major contributor to the increasing free energy of binding was a strong increase of binding enthalpy, whereas entropic contributions remained low and constant despite significant addition of lipophilicity.
使用表面等离子体共振和等温滴定量热法研究了二肽基肽酶（DPP）-4抑制剂（格列汀类）的结合动力学和热力学。格列汀类与DPP-4的结合是一个快速的静电驱动过程。解离速率通常较慢，部分原因是一些格列汀类形成了可逆共价键，部分原因是存在强烈且广泛的相互作用。由于强烈的离子相互作用和强烈的溶剂屏蔽氢键，所有格列汀类的结合均以焓为主导。使用一系列代表利格列汀先导优化程序中间体的同类分子，在化学结构逐步变化的背景下分析了缓慢结合动力学的起始和热力学特征的发展。所有化合物均迅速结合，因此亲和力和驻留时间的优化高度相关。结合自由能增加的主要贡献因素是结合焓的大幅增加，而尽管亲脂性显著增加，熵的贡献仍保持较低且恒定。
