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.
Highlights
As great things almost always start small, fragment-based lead discovery (FBLD) blossomed two decades after the first screening against a small set of low-molecular-weight compounds [1], dubbed fragments
We examine the success of FBLD in the most recently published fragment-derived leads targeting challenging protein–protein interactions
Using the aforementioned Nuclear magnetic resonance (NMR) screening settings, we have identified a series of hits for nine protein–protein interaction targets, with a primary screening hit rate of 0.7% ̆ 0.4%
Summary
As great things almost always start small, fragment-based lead discovery (FBLD) blossomed two decades after the first screening against a small set of low-molecular-weight compounds [1], dubbed fragments. Fragment-based screening samples a larger portion of chemical space, has a higher hit rate and ligand efficiency, and suffers less from false positive results when compared with HTS [3] It is intuitive for medicinal chemists to develop the fragment hits into potent leads. For some PPIs, the binding energy is mainly contributed by a limited number of residues that form a “hot spot” [29] This “hot spot” can accommodate small molecules identified from fragment-based screening, which are eventually evolved into potent leads. NMR approaches, which provide valuable structural information at the initial hit-to-lead stages, are delineated These include chemical shift perturbation to map the binding site and the emerging techniques of transferred paramagnetic relaxation enhancement (PRE) and pseudocontact shifts (PCSs) that determine the distance and/or orientation of fragment hits with respect to target proteins. We examine the success of FBLD in the most recently published fragment-derived leads targeting challenging protein–protein interactions
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