Process of Fragment-Based Lead Discovery—A Perspective from NMR
AbstractFragment-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
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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.
Ma R, Wang P, Wu J, Ruan K. Process of Fragment-Based Lead Discovery—A Perspective from NMR. Molecules. 2016; 21(7):854.Chicago/Turabian Style
Ma, Rongsheng; Wang, Pengchao; Wu, Jihui; Ruan, Ke. 2016. "Process of Fragment-Based Lead Discovery—A Perspective from NMR." Molecules 21, no. 7: 854.
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