Modulating Target Protein Biology Through the Re-mapping of Conformational Distributions Using Small Molecules.
allosteric
conformational distributions
conformational sampling
conformer
drug discovery
molecular dynamics
protein-protein interactions
small molecule
Journal
Frontiers in chemistry
ISSN: 2296-2646
Titre abrégé: Front Chem
Pays: Switzerland
ID NLM: 101627988
Informations de publication
Date de publication:
2021
2021
Historique:
received:
15
02
2021
accepted:
30
03
2021
entrez:
21
5
2021
pubmed:
22
5
2021
medline:
22
5
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34017820
doi: 10.3389/fchem.2021.668186
pmc: PMC8129178
doi:
Types de publication
Journal Article
Langues
eng
Pagination
668186Informations de copyright
Copyright © 2021 Lawson, MacCoss, Baeten, Macpherson, Shi and Henry.
Déclaration de conflit d'intérêts
AL, DB, AM, JS and AH are employed by the company UCB Pharma. MM was employed by Bohicket Consulting LLC.
Références
Nat Struct Mol Biol. 2014 Apr;21(4):397-404
pubmed: 24632569
Clin Pharmacol Ther. 2017 Jan;101(1):89-98
pubmed: 27806433
Nat Rev Drug Discov. 2012 Jun 29;11(7):519-25
pubmed: 22743979
Elife. 2020 Jul 22;9:
pubmed: 32697684
Bioorg Med Chem. 2014 Apr 1;22(7):2353-65
pubmed: 24593905
Curr Opin Struct Biol. 2018 Jun;50:1-8
pubmed: 29080471
Curr Opin Struct Biol. 2004 Dec;14(6):706-15
pubmed: 15582395
Eur J Med Chem. 2019 Apr 1;167:76-95
pubmed: 30769242
Acc Chem Res. 2020 Mar 17;53(3):654-661
pubmed: 32134250
J Med Chem. 2018 May 24;61(10):4283-4289
pubmed: 29140691
Biophys J. 2017 Jul 25;113(2):371-380
pubmed: 28746848
Molecules. 2015 Sep 10;20(9):16435-45
pubmed: 26378508
Drug Discov Today Technol. 2019 Dec;32-33:3-8
pubmed: 33386092
Biochem Soc Trans. 2020 Feb 28;48(1):271-280
pubmed: 31985743
Science. 1997 Oct 17;278(5337):497,499
pubmed: 9381145
Signal Transduct Target Ther. 2020 Sep 23;5(1):213
pubmed: 32968059
Nat Commun. 2019 Dec 19;10(1):5795
pubmed: 31857588
Prog Med Chem. 2020;59:181-249
pubmed: 32362328
Med Res Rev. 2019 Nov;39(6):2314-2342
pubmed: 30957264
Nat Rev Drug Discov. 2004 Apr;3(4):301-17
pubmed: 15060526
Nat Commun. 2021 Jan 25;12(1):582
pubmed: 33495441
Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5381-3
pubmed: 1608946
Isr J Chem. 2019 Feb;59(1-2):52-59
pubmed: 31123369
Adv Protein Chem Struct Biol. 2011;83:163-221
pubmed: 21570668
Nature. 2016 Jul 21;535(7612):448-52
pubmed: 27409812
Int J Mol Sci. 2018 Mar 07;19(3):
pubmed: 29518978
Molecules. 2020 Mar 18;25(6):
pubmed: 32197324
Nat Commun. 2021 Jan 25;12(1):583
pubmed: 33495445
Science. 1985 Jun 14;228(4705):1315-7
pubmed: 4001944
Drug Discov Today. 2020 Sep;25(9):1693-1701
pubmed: 32592867
Annu Rev Biochem. 2018 Jun 20;87:479-502
pubmed: 29328784
Chemistry. 2020 Apr 9;26(21):4656-4670
pubmed: 31746512