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Small molecules, big targets: drug discovery faces the protein–protein interaction challenge

Key Points

  • Protein–protein interactions (PPIs) are increasingly being targeted by drug discovery groups, and there exists great scope for therapeutic modulation of this target class in disease.

  • The array of structurally interacting elements through which proteins interact with one another is wide and resists clear-cut classification. However, broad divisions can be made by grouping interactions based upon the globular or peptidic nature of the proteins.

  • Some strategies for developing inhibitors against a given PPI may have more traction against certain classes of PPIs than others; for example, fragment-based drug discovery has shown particular promise in targeting bromodomains, as have peptide mimetics in mimicking β-strands.

  • We examine case studies representative of the various structural types of PPI and discuss the lessons learnt from each.

  • A summary of current status of inhibitors in clinical trials against different targets is presented.

Abstract

Protein–protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.

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Figure 1: Structural classification of protein–protein interactions.
Figure 2: Strategies for developing peptidomimetics.
Figure 3: Interaction between a globular protein and a helical peptide with a discontinuous epitope: BCL-2–BH3 domain.
Figure 4: Interaction between a globular protein and a peptide with a continuous epitope: XIAP–caspase 9.
Figure 5: Interaction between a globular protein and a peptide with a continuous epitope: KEAP1–NRF2.
Figure 6: Interaction between a globular protein and globular protein through a discontinuous epitope: IL-2–IL-2R.
Figure 7: Interaction between a globular protein and a peptide with an anchoring residue: BRD4.

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Acknowledgements

The authors thank T. Blundell and H. Jubb for helpful discussions. J.S., D.E.S. and A.R.B. thank the Wellcome Trust for funding.

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Correspondence to Chris Abell or John Skidmore.

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J.S. owns shares in GlaxoSmithKline. C.A. is co-founder and advisor for Astex Pharmaceuticals. A.B. is an employee of Vertex.

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Glossary

Globular protein

A protein whose peptide chains are folded to form a broadly spherical shape. This term is often extended to mean a non-membrane-bound protein in which multiple regions of the peptide chain combine to give a defined tertiary structure with one or more binding or active sites.

Hot spots

Regions of a binding surface that contribute a disproportionately large amount to the interaction energy of a pair of proteins or a protein and a ligand.

Alanine scanning

A set of experiments in which amino acids in a protein are sequentially mutated to Ala in order to estimate the contribution of the individual side chains to the binding energy of a protein–protein interaction.

Discontinuous epitope

A binding site at which amino acids from different regions of the protein sequence combine to interact with the partner protein. For example, periodic side chains on one face of a helix or residues from a group of neighbouring chains in a globular protein.

Intrinsically disordered peptide

A peptide lacking a fixed 3D structure when in a monomeric state. Such species may adopt a more ordered structure when interacting with other proteins or ligands.

Druggability

An assessment of the ease with which a drug can be developed to interact with a given protein target. In this case, it has a relatively narrow meaning — namely the ease of generating a small molecule with reasonable affinity.

Pharmacophore

The features of a ligand responsible for its binding to a protein, which are reduced to an abstract representation lacking an underlying framework of bonds or rings

Apoptosis

Programmed cell death controlled by a complex network of interactions including protein–protein interactions.

Ubiquitylation

The attachment of a small protein, ubiquitin, onto another protein — often as a prelude to controlled degradation of the labelled protein.

ADMET

Absorption, distribution, metabolism, excretion and toxicity — key properties of a potential drug that depend, in part, on the physicochemical properties of a molecule.

PDZ domain

A protein domain containing a series of Gly-Leu-Gly-Phe repeating units. Named after the postsynaptic density protein 95 (PSD95), the Drosophilia melanogaster tumour suppressor discs large 1 (Dlg1; also known as Dlg-A) and the tight-junction associated protein zonula occludens 1 (ZO1).

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Scott, D., Bayly, A., Abell, C. et al. Small molecules, big targets: drug discovery faces the protein–protein interaction challenge. Nat Rev Drug Discov 15, 533–550 (2016). https://doi.org/10.1038/nrd.2016.29

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