TY - JOUR
T1 - Modulating Target Protein Biology Through the Re-mapping of Conformational Distributions Using Small Molecules
AU - Lawson, Alastair D. G.
AU - MacCoss, Malcolm
AU - Baeten, Dominique L.
AU - Macpherson, Alex
AU - Shi, Jiye
AU - Henry, Alistair J.
N1 - Funding Information: The authors declare that this study received funding from UCB Pharma. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. Publisher Copyright: © Copyright © 2021 Lawson, MacCoss, Baeten, Macpherson, Shi and Henry. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5/4
Y1 - 2021/5/4
N2 - 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.
AB - 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.
KW - allosteric
KW - conformational distributions
KW - conformational sampling
KW - conformer
KW - drug discovery
KW - molecular dynamics
KW - protein-protein interactions
KW - small molecule
UR - http://www.scopus.com/inward/record.url?scp=85105990881&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fchem.2021.668186
DO - https://doi.org/10.3389/fchem.2021.668186
M3 - Article
C2 - 34017820
SN - 2296-2646
VL - 9
JO - Frontiers in Chemistry
JF - Frontiers in Chemistry
M1 - 668186
ER -