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Implications of protein flexibility for drug discovery

Key Points

  • A large number of pharmaceutically relevant targets have been shown to be flexible, which are collected in this article. This comprehensive list of present and historical pharmaceutical targets provides the basis for questioning the relevance of the rigid receptor hypothesis, which is commonly used during in silico drug design.

  • The role of protein flexibility in future pharmaceutical targets is likely to be even greater than in the past. Presently under-exploited target classes, such as ion channels, nuclear hormone receptors and transporters, have functions that are inextricably bound up with their structural flexibility.

  • This article uses illustrative examples to discuss the implications of protein flexibility in drug discovery, and highlights how it could be exploited in drug design.

Abstract

Proteins are in constant motion between different conformational states with similar energies. This has often been ignored in drug design. However, protein flexibility is fundamental to understanding the ways in which drugs exert biological effects, their binding-site location, binding orientation, binding kinetics, metabolism and transport. Protein flexibility allows increased affinity to be achieved between a drug and its target. This is crucial, because the lipophilicity and number of polar interactions allowed for an oral drug is limited by absorption, distribution, metabolism and toxicology considerations.

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Figure 1: Protein mobility and ligand binding.
Figure 2: Novel conformation of renin observed on binding a non-peptidomimetic ligand.
Figure 3: Conformational induction of proteins by ligands.
Figure 4: Common mechanisms for domain movement.
Figure 5: Multiple conformations of a single residue.
Figure 6: Chemical structures of various compounds highlighted.
Figure 7: Movement of a large number of residues: example 1.
Figure 8: Structurally diverse ligands in a single binding site.
Figure 9: Surprising orientations of structurally similar ligands.
Figure 10: Forcing new conformations.

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Acknowledgements

I wish to acknowledge Dr A. M. Davis for invaluable discussions concerning this manuscript, and Dr S. St-Gallay for assistance with preparation of the figures.

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FURTHER INFORMATION

Database of Macromolecular Movements with Associated Tools for Geometric Analysis

Protein Data Bank

Glossary

π–π STACKING

Weak non-covalent interactions between the faces of two aromatic moieties, one of which is electron rich and the other electron deficient.

CATION–π INTERACTION

A surprisingly strong non-covalent force in which cations bind to the π face of aromatic rings. The interaction can be considered an electrostatic attraction between a positive charge and the quadrupole moment of the aromatic moiety, typically the side chains of phenylalanine, tyrosine and tryptophan residues.

TRANSITION-STATE ANALOGUE

A compound designed to mimic the properties or geometry of the transition state of an enzymatic reaction, but which is stable to processing by the enzyme. Such compounds inhibit the enzyme by binding more tightly than the natural substrate(s).

χ1 ANGLE

χ1 is the torsional angle that describes the conformation(s) of atoms which form the side-chain of a particular amino-acid residue relative to the peptide backbone.

B-FACTORS

B-factors (also known as temperature factors) model the effect of static and dynamic disorder associated with an atom when it is observed by X-ray analysis. They are related to the atom's mean square displacement during observation.

APO FORM

Enzyme (receptor) in its free state without substrates or inhibitors bound.

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Teague, S. Implications of protein flexibility for drug discovery. Nat Rev Drug Discov 2, 527–541 (2003). https://doi.org/10.1038/nrd1129

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