Authors: Singh, Himanshu
Das, Chandan K.
Vasa, Suresh K.
Grohe, Kristof
Schäfer, Lars V.
Linser, Rasmus
Title: The active site of a prototypical “rigid” drug target is marked by extensive conformational dynamics
Language (ISO): en
Abstract: 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.
Subject Headings: Carbonic anhydrase II
Conformational exchange dynamics
Drug discovery
NMR spectroscopy
Protein structure
Issue Date: 2020-09-23
Rights link:
Appears in Collections:Physikalische Chemie

Files in This Item:
File Description SizeFormat 
anie.202009348.pdf2.57 MBAdobe PDFView/Open

This item is protected by original copyright

This item is licensed under a Creative Commons License Creative Commons