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A decade of fragment-based drug design: strategic advances and lessons learned

Nature Reviews Drug Discovery volume 6, pages 211–219 (2007)Cite this article

Key Points

  • Fragment-based drug design is based on screening smaller numbers of compounds (typically several thousand) in the hopes of finding low-affinity fragments (Kd values in the high micromolar to millimolar range), in contrast to conventional high-throughput screening (HTS), which attempts to evaluate as many compounds as technologically possible (typically a million or more) in the hopes of finding relatively potent drug leads (Kd values ideally less than 1 μM).

  • The combination of broader sampling of the potential chemical universe than HTS and increased hit rates for molecules of low complexity makes fragment-based screening a powerful tool for lead generation. Fragment-based screening is also less prone to artefacts as the low-molecular-mass compounds tend to be more soluble and the methods of detection are simpler and more robust.

  • Two-dimensional, isotope-edited nuclear magnetic resonance (NMR) spectroscopy was the first approach used in fragment-based drug design. It is well suited to this purpose as NMR chemical shifts are exquisitely sensitive to ligand binding, and problems with compound interference can be solved by spectral editing.

  • During the past decade, the popularity of fragment-based screening has grown at a remarkable rate in both industry and academia. A range of different strategies have been developed, including alternative NMR-based approaches that obviate the need for isotope labelling, approaches based on X-ray-crystallography and fragment tethering, which are discussed here.

  • The ability to obtain NMR or X-ray crystal structures on fragment leads has a dramatic influence on the success of fragment-based drug design.

  • The successful applications of fragment-based drug design have provided ample support that the use of fragments could, in many cases, be the most direct route to the best achievable balance between potency and pharmacokinetics.

Abstract

Since the early 1990s, several technological and scientific advances — such as combinatorial chemistry, high-throughput screening and the sequencing of the human genome — have been heralded as remedies to the problems facing the pharmaceutical industry. The use of these technologies in some form is now well established at most pharmaceutical companies; however, the return on investment in terms of marketed products has not met expectations. Fragment-based drug design is another tool for drug discovery that has emerged in the past decade. Here, we describe the development and evolution of fragment-based drug design, analyse the role that this approach can have in combination with other discovery technologies and highlight the impact that fragment-based methods have made in progressing new medicines into the clinic.

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Figure 1: Applications of the 'SAR by NMR' method for fragment-based design.
Figure 2: Trends in the application of fragment-based screening.
Figure 3: Percentage of protein-binding sites that can be targeted with small, drug-like molecules as a function of hit rate from NMR-based fragment screening.
Figure 4: Comparing high-throughput screening and fragment-based screening.
Figure 5: Importance of structural information to the success of fragment-based drug design.
Figure 6: Relationship between potency and molecular mass during fragment optimization.

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Acknowledgements

The authors would like to thank R. Artis (Plexxikon), M. Congreve (Astex), D. Erlanson (Sunesis), R. Hubbard (Vernalis), W. Jahnke (Novartis), C. Lepre (Vertex), and D. Wyss (Schering–Plough) for help in gathering the data for Table 1.

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Authors and Affiliations

  1. Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, 60064, Illinois, USA

    Philip J. Hajduk & Jonathan Greer

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Correspondence to Philip J. Hajduk.

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Glossary

Forward and reverse genetics

Forward genetics approaches involve proceeding from phenotype to genotype by positional cloning or candidate-gene analysis. Reverse genetics approaches involve proceeding from genotype to phenotype through gene-manipulation techniques.

New chemical entity

A medication containing an active ingredient that has not been previously approved for marketing in any form.

Kd values

The equilibrium dissociation constant of a compound that reflects the concentration needed to reach half-maximal saturation of binding sites. Kd reflects the strength of binding of a compound to its specific binding site.

Pharmacophore

The ensemble of steric and electronic features that is necessary to ensure optimal interactions with a specific biological target structure and to trigger (or to block) its biological response.

Two-dimensional, isotope-edited nuclear magnetic resonance (NMR) spectroscopy

NMR experiments that exploit nuclear coupling to correlate the chemical shifts of protons with other NMR-active nuclei, most often carbon-13 or nitrogen-15.

Structure–activity relationships

Correlations that are constructed between the features of chemical structure in a set of candidate compounds and parameters of biological activity, such as potency, selectivity and toxicity.

IC50 value

The half maximal inhibitory concentration. Represents the concentration of an inhibitor that is required for 50% inhibition of a biological or molecular process.

Druggability

The ability of a target to be modulated by a lead candidate that has the requisite physicochemical and absorption, distribution, metabolism and excretion properties for development as a drug candidate.

Rule-of-five

The 'rule of five' identifies several key properties that should be considered for compounds with oral delivery in mind. These properties are molecular mass <500 Da, cLogP <5, number of hydrogen-bond donors <5 and number of hydrogen-bond acceptors <10.

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Hajduk, P., Greer, J. A decade of fragment-based drug design: strategic advances and lessons learned. Nat Rev Drug Discov 6, 211–219 (2007). https://doi.org/10.1038/nrd2220

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