Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Str. 4a, 44227, Dortmund, Germany.
Faculty for Chemistry and Pharmacy, Ludwig-Maximilians-University Munich, Butenandtstr. 5-13, 81377, Munich, Germany.
Angew Chem Int Ed Engl. 2020 Dec 14;59(51):22916-22921. doi: 10.1002/anie.202009348. Epub 2020 Nov 16.
Drug discovery, in particular optimization of candidates using medicinal chemistry, is generally guided by structural biology. However, for optimizing binding kinetics, relevant for efficacy and off-target effects, information on protein motion is important. Herein, we demonstrate for the prototypical textbook example of an allegedly "rigid protein" that substantial active-site dynamics have generally remained unrecognized, despite thousands of medicinal-chemistry studies on this model over decades. Comparing cryogenic X-ray structures, solid-state NMR on micro-crystalline protein at room temperature, and solution NMR structure and dynamics, supported by MD simulations, we show that under physiologically relevant conditions the pocket is in fact shaped by pronounced open/close conformational-exchange dynamics. The study, which is of general significance for pharmacological research, evinces a generic pitfall in drug discovery routines.
药物发现，特别是使用药物化学对候选药物进行优化，通常以结构生物学为指导。然而，为了优化与疗效和脱靶效应相关的结合动力学，了解蛋白质运动的信息很重要。在这里，我们展示了一个原型教科书案例，即所谓的“刚性蛋白质”，尽管几十年来对这个模型进行了数千次药物化学研究，但普遍仍未认识到其活性部位的大量动力学。通过比较低温 X 射线结构、室温下微晶态蛋白质的固态 NMR、溶液 NMR 结构和动力学，并辅以 MD 模拟，我们表明在生理相关条件下，口袋实际上是由明显的开/合构象交换动力学塑造的。这项研究对于药理学研究具有普遍意义，揭示了药物发现常规中的一个普遍陷阱。
