INPHARMA‐Based Determination of Ligand Binding Modes at α1‐Adrenergic Receptors Explains the Molecular Basis of Subtype Selectivity

• Published in: Chemistry : a European journal Vol. 26; no. 51; pp. 11796 - 11805
• Main Authors: Vaid, Tasneem M., Chalmers, David K., Scott, Daniel J., Gooley, Paul R.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 10.09.2020
• Subjects: Adrenergic receptors; Agonists; Binding; Chemistry; Crystal structure; Drug development; Epinephrine; G protein-coupled receptors; interligand NOEs for pharmacophore mapping (INPHARMA); intermolecular ligand–ligand NOEs; Ligands; Mapping; Molecular dynamics; NMR; NMR spectroscopy; Nuclear magnetic resonance; Proteins; Receptors; Receptors (physiology); Selectivity; Tr-NOESY; ligand binding conformation; GPCR; NMR; INPHARMA
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202000642

The structural poses of ligands that bind weakly to protein receptors are challenging to define. In this work we have studied ligand interactions with the adrenoreceptor (AR) subtypes, α1A‐AR and α1B‐AR, which belong to the G protein‐coupled receptor (GPCR) superfamily, by employing the solution‐based ligand‐observed NMR method interligand NOEs for pharmacophore mapping (INPHARMA). A lack of receptor crystal structures and of subtype‐selective drugs has hindered the definition of the physiological roles of each subtype and limited drug development. We determined the binding pose of the weakly binding α1A‐AR‐selective agonist A‐61603 relative to an endogenous agonist, epinephrine, at both α1A‐AR and α1B‐AR. The NMR experimental data were quantitatively compared, by using SpINPHARMA, to the back‐calculated spectra based on ligand poses obtained from all‐atom molecular dynamics simulations. The results helped mechanistically explain the selectivity of (R)‐A‐61603 towards α1A‐AR, thus demonstrating an approach for targeting subtype selectivity in ARs. To question a pose: Ligand‐detected NMR spectroscopy in combination with molecular dynamics simulations presents a powerful approach to determining the binding pose of ligands binding weakly to G protein‐coupled receptors. The NMR‐computational procedure was applied to determine the pose of a subtype‐specific ligand targeted to the α1‐adrenoreceptors.