title: Process of Fragment-Based Lead Discovery-A Perspective from NMR.
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.
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei 230027, Anhui, China. mrs1988@mail.ustc.edu.cn.
authors.forename: Rongsheng
authors.initials: R
authors.lastname: Ma
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei 230027, Anhui, China. wpc1009@mail.ustc.edu.cn.
authors.forename: Pengchao
authors.initials: P
authors.lastname: Wang
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei 230027, Anhui, China. wujihui@ustc.edu.cn.
authors.forename: Jihui
authors.initials: J
authors.lastname: Wu
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei 230027, Anhui, China. kruan@ustc.edu.cn.
authors.forename: Ke
authors.initials: K
authors.lastname: Ruan
mesh_terms: D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D054852:Small Molecule Libraries
keywords: NMR spectroscopy; fragment based lead discovery; protein–protein interaction