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Twenty years on: the impact of fragments on drug discovery

Key Points

  • Fragment-based drug discovery (FBDD) is playing an increasingly important part in delivering candidates to the clinic.

  • Compared with screens of lead- or drug-sized molecules, fragments allow for a more thorough search of chemical space and can lead to superior molecules.

  • Fragments can provide fundamental insights into molecular recognition between proteins and ligands.

  • Rigorous use of multiple biophysical techniques is essential to identify and validate fragments.

  • Early and creative medicinal chemistry is needed to transform a low-affinity fragment into a lead molecule.

  • FBDD can be integrated with other lead discovery methods to tackle difficult problems.

Abstract

After 20 years of sometimes quiet growth, fragment-based drug discovery (FBDD) has become mainstream. More than 30 drug candidates derived from fragments have entered the clinic, with two approved and several more in advanced trials. FBDD has been widely applied in both academia and industry, as evidenced by the large number of papers from universities, non-profit research institutions, biotechnology companies and pharmaceutical companies. Moreover, FBDD draws on a diverse range of disciplines, from biochemistry and biophysics to computational and medicinal chemistry. As the promise of FBDD strategies becomes increasingly realized, now is an opportune time to draw lessons and point the way to the future. This Review briefly discusses how to design fragment libraries, how to select screening techniques and how to make the most of information gleaned from them. It also shows how concepts from FBDD have permeated and enhanced drug discovery efforts.

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Figure 1: Discovery of vemurafenib.
Figure 2: Discovery of AZD5363.
Figure 3: Discovery of new ligand chemotypes for the β1 adrenergic receptor.
Figure 4: Discovery of the B cell lymphoma 2-selective candidate ABT-199.
Figure 5: Fragments binding to RAS.
Figure 6: Discovery of a novel binding site in Hepatitis C virus NS3.

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Acknowledgements

The Authors thank U. Schopfer and the anonymous reviewers for helpful comments and suggestions on the manuscript.

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Correspondence to Daniel A. Erlanson.

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Competing interests

D.A.E. is a co-founder, employee and shareholder of Carmot Therapeutics, Inc. R.H. is an employee and shareholder of Vernalis (R&D) Ltd. W.J. is an employee and shareholder of Novartis AG. H.J. is an employee of Astex Pharmaceuticals.

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The logarithm of partition coefficient between n-octanol and water. cLogP is a measure of lipophilicity.

Chemotype

A chemical structure motif or primary substructure that is common to a group of compounds.

Michael acceptors

An activated carbon–carbon double bond that is susceptible to nucleophilic attack.

Surface plasmon resonance

(SPR). An assay that detects binding between a surface- immobilized molecule (such as a protein) and a molecule in solution (such as a fragment).

Ligand-observed NMR

Detection of ligand binding by nuclear magnetic resonance (NMR) spectroscopy using methods such as saturation transfer difference (STD) NMR (to measure transfer of magnetization between protein and ligand), T1ρ relaxation (to exploit faster relaxation of bound ligands), waterLOGSY (to detect binding by transfer of magnetization between ligand and bound water) or 19F T2 (to detect faster relaxation of fluorinated bound ligands).

ALARM

A nuclear magnetic resonance (NMR)-based method to detect false positives, such as pan-assay interference compounds (PAINS).

Pan-assay interference compounds

(PAINS). Compounds containing substructures that give rise to apparent but artefactual activity in assays. The specific mechanisms vary and are not always known, but include forming covalent adducts with the protein or producing hydrogen peroxide.

Thermal shift assays

(TSAs). Assays, such as differential scanning fluorimetry, that measure the denaturation (or melting) temperature of a protein, which is often increased in the presence of a binding partner.

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Erlanson, D., Fesik, S., Hubbard, R. et al. Twenty years on: the impact of fragments on drug discovery. Nat Rev Drug Discov 15, 605–619 (2016). https://doi.org/10.1038/nrd.2016.109

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