Modulating Target Protein Biology Through the Re-mapping of Conformational Distributions Using Small Molecules

Alastair D G Lawson; Malcolm MacCoss; Dominique L Baeten; Alex Macpherson; Jiye Shi; Alistair J Henry

doi:10.3389/fchem.2021.668186

Modulating Target Protein Biology Through the Re-mapping of Conformational Distributions Using Small Molecules

Front Chem. 2021 May 4:9:668186. doi: 10.3389/fchem.2021.668186. eCollection 2021.

Authors

Alastair D G Lawson¹, Malcolm MacCoss², Dominique L Baeten¹, Alex Macpherson¹, Jiye Shi¹, Alistair J Henry¹

Affiliations

¹ UCB Pharma, Slough, United Kingdom.
² Bohicket Consulting LLC, Seabrook Island, SC, United States.

Abstract

Over the last 10 years considerable progress has been made in the application of small molecules to modulating protein-protein interactions (PPIs), and the navigation from "undruggable" to a host of candidate molecules in clinical trials has been well-charted in recent, comprehensive reviews. Structure-based design has played an important role in this scientific journey, with three dimensional structures guiding medicinal chemistry efforts. However, the importance of two additional dimensions: movement and time is only now being realised, as increasing computing power, closely aligned with wet lab validation, is applied to the challenge. Protein dynamics are fundamental to biology and disease, and application to PPI drug discovery has massively widened the scope for new chemical entities to influence function from allosteric, and previously unreported, sites. In this forward-looking perspective we highlight exciting, new opportunities for small molecules to modulate disease biology, by adjusting the frequency profile of natural conformational sampling, through the stabilisation of clinically desired conformers of target proteins.

Keywords: allosteric; conformational distributions; conformational sampling; conformer; drug discovery; molecular dynamics; protein-protein interactions; small molecule.