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Design of Drug Efficacy Guided by Free Energy Simulations of the β2-Adrenoceptor
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- Panel, Nicolas (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Beräkningsbiologi och bioinformatik,Uppsala Univ, Dept Cell & Mol Biol, Sci Life Lab, S-75124 Uppsala, Sweden.
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- Vo, Duc Duy (author)
- Uppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab
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- Kahlous, Nour Aldin (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Beräkningsbiologi och bioinformatik,Uppsala Univ, Dept Cell & Mol Biol, Sci Life Lab, S-75124 Uppsala, Sweden.
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- (creator_code:org_t)
- 2023-03-13
- 2023
- English.
- In: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 62:22
- Journal article (peer-reviewed)
Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biofysik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biophysics (hsv//eng)
Keyword
- Agonist
- Drug Design
- Free Energy Perturbation
- G-Protein-Coupled Receptor
- Molecular Dynamics
- β Adrenergic Receptor 2
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- art (subject category)
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- Carlsson, Jens
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