Fragment evolution for GPCRs: The role of secondary binding sites in optimization

Chevillard, Florent; Kelemen, Ádám; Baker, Jillian G.; Aranyodi, Vivien A.; Balzer, Frank; Kolb, Peter; Keserű, György M.

Abstract

We developed a docking-based fragment evolution approach that extends orthosteric fragments towards a less conserved secondary binding pocket of GPCRs. Evaluating 13 000 extensions for the β1- and β2-adrenergic receptors we synthesized and tested 112 bitopic molecules. Our results confirmed the positive contribution of the secondary binding pocket to both potency and selectivity optimizations.

Citation

Chevillard, F., Kelemen, Á., Baker, J. G., Aranyodi, V. A., Balzer, F., Kolb, P., & Keserű, G. M. (2021). Fragment evolution for GPCRs: The role of secondary binding sites in optimization. Chemical Communications, 57(81), 10516-10519. https://doi.org/10.1039/d1cc04636e

• Journal Article Type: Article
• Acceptance Date: Sep 9, 2021
• Online Publication Date: Sep 10, 2021
• Publication Date: Oct 18, 2021
• Deposit Date: Mar 10, 2025
• Publicly Available Date: Mar 10, 2025
• Journal: Chemical Communications
• Print ISSN: 1359-7345
• Electronic ISSN: 1364-548X
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 57
• Issue: 81
• Pages: 10516-10519
• DOI: https://doi.org/10.1039/d1cc04636e
• Public URL: https://nottingham-repository.worktribe.com/output/6615163
• Publisher URL: https://pubs.rsc.org/en/content/articlelanding/2021/cc/d1cc04636e