Fragment‐Based Drug Discovery

Renaud, Jean‐Paul; Neumann, Thomas; Hijfte, Luc Van

doi:10.1002/9781118771723.ch8

Cited by 3 publications

(3 citation statements)

References 96 publications

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“…Surface plasmon resonance (SPR) technique is a very powerful tool for the determination of binding events [38]. SPR can be used to measure the binding affinity, specificity, and kinetic parameters of biomolecular interactions between a variety of proteins, DNA/RNA, and small/complex molecules [39,40]. The target protein is first immobilized on a gold or silver sensor surface.…”

Section: Fragment Hit Identificationmentioning

confidence: 99%

Concepts and Core Principles of Fragment-Based Drug Design

et al. 2019

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In this review, a general introduction to fragment-based drug design and the underlying concepts is given. General considerations and methodologies ranging from library selection/construction over biophysical screening and evaluation methods to in-depth hit qualification and subsequent optimization strategies are discussed. These principles can be generally applied to most classes of drug targets. The examples given for fragment growing, merging, and linking strategies at the end of the review are set in the fields of enzyme-inhibitor design and macromolecule–macromolecule interaction inhibition. Building upon the foundation of fragment-based drug discovery (FBDD) and its methodologies, we also highlight a few new trends in FBDD.

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Section: Fragment Hit Identificationmentioning

confidence: 99%

Concepts and Core Principles of Fragment-Based Drug Design

et al. 2019

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“…To this end, we pursued the fragment screening approach, motivated by its emerging promise in revealing novel binding pockets and providing good chemistry starting points. 35 We coupled this approach with X-ray crystallography, to provide direct structural readout as part of the screening process. 36 We found that hGALK1 co-crystallized with galactose and T2 produced the required quantity (crystals in the hundreds) and diffraction quality (consistently better than 2.5 Å) for the screening campaign.…”

Section: Resultsmentioning

confidence: 99%

“…As hGALK1 belongs to the kinase superfamily, we recognize that developing inhibitors that are not ATP-competitive could be beneficial for downstream optimization of pharmacokinetics/dynamics. To this end, we pursued the fragment screening approach, motivated by its emerging promise in revealing novel binding pockets and providing good chemistry starting points . We coupled this approach with X-ray crystallography, to provide direct structural readout as part of the screening process .…”

Section: Resultsmentioning

confidence: 99%

Fragment Screening Reveals Starting Points for Rational Design of Galactokinase 1 Inhibitors to Treat Classic Galactosemia

et al. 2021

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Classic galactosemia is caused by loss-of-function mutations in galactose-1-phosphate uridylyltransferase (GALT) that lead to toxic accumulation of its substrate, galactose-1-phosphate. One proposed therapy is to inhibit the biosynthesis of galactose-1-phosphate, catalyzed by galactokinase 1 (GALK1). Existing inhibitors of human GALK1 (hGALK1) are primarily ATP-competitive with limited clinical utility to date. Here, we determined crystal structures of hGALK1 bound with reported ATP-competitive inhibitors of the spiro-benzoxazole series, to reveal their binding mode in the active site. Spurred by the need for additional chemotypes of hGALK1 inhibitors, desirably targeting a nonorthosteric site, we also performed crystallography-based screening by soaking hundreds of hGALK1 crystals, already containing active site ligands, with fragments from a custom library. Two fragments were found to bind close to the ATP binding site, and a further eight were found in a hotspot distal from the active site, highlighting the strength of this method in identifying previously uncharacterized allosteric sites. To generate inhibitors of improved potency and selectivity targeting the newly identified binding hotspot, new compounds were designed by merging overlapping fragments. This yielded two micromolar inhibitors of hGALK1 that were not competitive with respect to either substrate (ATP or galactose) and demonstrated good selectivity over hGALK1 homologues, galactokinase 2 and mevalonate kinase. Our findings are therefore the first to demonstrate inhibition of hGALK1 from an allosteric site, with potential for further development of potent and selective inhibitors to provide novel therapeutics for classic galactosemia.

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Biophysics in drug discovery: impact, challenges and opportunities

Renaud

Chung

Danielson

et al. 2016

Nat Rev Drug Discov

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323

251

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Over the past 25 years, biophysical technologies such as X-ray crystallography, nuclear magnetic resonance spectroscopy, surface plasmon resonance spectroscopy and isothermal titration calorimetry have become key components of drug discovery platforms in many pharmaceutical companies and academic laboratories. There have been great improvements in the speed, sensitivity and range of possible measurements, providing high-resolution mechanistic, kinetic, thermodynamic and structural information on compound-target interactions. This Review provides a framework to understand this evolution by describing the key biophysical methods, the information they can provide and the ways in which they can be applied at different stages of the drug discovery process. We also discuss the challenges for current technologies and future opportunities to use biophysical methods to solve drug discovery problems.

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Fragment‐Based Drug Discovery

Cited by 3 publications

References 96 publications

Concepts and Core Principles of Fragment-Based Drug Design

Concepts and Core Principles of Fragment-Based Drug Design

Fragment Screening Reveals Starting Points for Rational Design of Galactokinase 1 Inhibitors to Treat Classic Galactosemia

Biophysics in drug discovery: impact, challenges and opportunities

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