期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 59, 期 51, 页码 22916-22921出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202009348
关键词
carbonic anhydrase II; conformational exchange dynamics; drug discovery; NMR spectroscopy; protein structure
资金
- European Union's Horizon 2020 research and innovation program under the Marie Skodowska-Curie grant [801459 - FP-RESOMUS]
- Deutsche Forschungsgemeinschaft (DFG) [SFB 1309-325871075, SFB 749-27112786]
- Deutsche Forschungsgemeinschaft (DFG) im Rahmen der Exzellenzstrategie des Bundes und der Lander-EXC 2033 [390677874 - RESOLV, EXC 114-24286268 - CiPSM]
- Project DEAL
- Projekt DEAL
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.
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