Design of Drug Efficacy Guided by Free Energy Simulations of the β2-Adrenoceptor

Panel N, Vo DD, Kahlous NA, Hübner H, Tiedt S, Matricon P, Pacalon J, Fleetwood O, Kampen S, Luttens A, Delemotte L, Kihlberg J, Gmeiner P, Carlsson J (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Angewandte Chemie International Edition Wiley

DOI: 10.1002/anie.202218959

Abstract

G-protein-coupled receptors (GPCRs) play important roles in physiological processes and are modulated by drugs that either activate or block signaling. Rational design of the pharmacological efficacy profiles of GPCR ligands could enable the development of more efficient drugs, but is challenging even if high-resolution receptor structures are available. We performed molecular dynamics simulations of the β2 adrenergic receptor in active and inactive conformations to assess if binding free energy calculations can predict differences in ligand efficacy for closely related compounds. Previously identified ligands were successfully classified into groups with comparable efficacy profiles based on the calculated shift in ligand affinity upon activation. A series of ligands were then predicted and synthesized, leading to the discovery of partial agonists with nanomolar potencies and novel scaffolds. Our results demonstrate that free energy simulations enable design of ligand efficacy and the same approach can be applied to other GPCR drug targets.

Authors with CRIS profile

Harald Hübner Lehrstuhl für Pharmazeutische Chemie Stephanie Tiedt Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie

Involved external institutions

Uppsala University SE Sweden (SE) Royal Institute of Technology / Kungliga Tekniska Högskolan (KTH) SE Sweden (SE)

How to cite

APA:

Panel, N., Vo, D.D., Kahlous, N.A., Hübner, H., Tiedt, S., Matricon, P.,... Carlsson, J. (2023). Design of Drug Efficacy Guided by Free Energy Simulations of the β2-Adrenoceptor. Angewandte Chemie International Edition. https://doi.org/10.1002/anie.202218959

MLA:

Panel, Nicolas, et al. "Design of Drug Efficacy Guided by Free Energy Simulations of the β2-Adrenoceptor." Angewandte Chemie International Edition (2023).

BibTeX: Download