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Molecules 2016, 21(7), 854; doi:10.3390/molecules21070854

Process of Fragment-Based Lead Discovery—A Perspective from NMR

Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei 230027, Anhui, China
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Academic Editors: Raymond S. Norton and Martin J. Scanlon
Received: 28 March 2016 / Revised: 22 May 2016 / Accepted: 24 May 2016 / Published: 16 July 2016
(This article belongs to the Special Issue Developments in Fragment-Based Lead Discovery)
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Abstract

Fragment-based lead discovery (FBLD) has proven fruitful during the past two decades for a variety of targets, even challenging protein–protein interaction (PPI) systems. Nuclear magnetic resonance (NMR) spectroscopy plays a vital role, from initial fragment-based screening to lead generation, because of its power to probe the intrinsically weak interactions between targets and low-molecular-weight fragments. Here, we review the NMR FBLD process from initial library construction to lead generation. We describe technical aspects regarding fragment library design, ligand- and protein-observed screening, and protein–ligand structure model generation. For weak binders, the initial hit-to-lead evolution can be guided by structural information retrieved from NMR spectroscopy, including chemical shift perturbation, transferred pseudocontact shifts, and paramagnetic relaxation enhancement. This perspective examines structure-guided optimization from weak fragment screening hits to potent leads for challenging PPI targets. View Full-Text
Keywords: fragment based lead discovery; NMR spectroscopy; protein–protein interaction fragment based lead discovery; NMR spectroscopy; protein–protein interaction
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Ma, R.; Wang, P.; Wu, J.; Ruan, K. Process of Fragment-Based Lead Discovery—A Perspective from NMR. Molecules 2016, 21, 854.

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