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INPHARMA‐Based Determination of Ligand Binding Modes at α 1 ‐Adrenergic Receptors Explains the Molecular Basis of Subtype Selectivity
Author(s) -
Vaid Tasneem M.,
Wu FengJie,
Chalmers David K.,
Scott Daniel J.,
Gooley Paul R.
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202000642
Subject(s) - pharmacophore , chemistry , selectivity , ligand (biochemistry) , agonist , g protein coupled receptor , receptor , functional selectivity , molecular dynamics , stereochemistry , binding site , biochemistry , computational chemistry , catalysis
Abstract 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, α 1A ‐AR and α 1B ‐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 α 1A ‐AR‐selective agonist A‐61603 relative to an endogenous agonist, epinephrine, at both α 1A ‐AR and α 1B ‐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 α 1A ‐AR, thus demonstrating an approach for targeting subtype selectivity in ARs.