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Ligand‐binding affinity of alternative conformers of human β 2 ‐adrenergic receptor in the presence of intracellular loop 3 ( ICL 3) and their potential use in virtual screening studies
Author(s) -
Dilcan Gonca,
Doruker Pemra,
Akten Ebru Demet
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13478
Subject(s) - conformational isomerism , virtual screening , docking (animal) , chemistry , stereochemistry , ligand (biochemistry) , inverse agonist , binding site , pharmacophore , receptor , computational biology , molecular dynamics , computational chemistry , agonist , biochemistry , biology , molecule , medicine , nursing , organic chemistry
This study investigates the structural distinctiveness of orthosteric ligand‐binding sites of several human β 2 adrenergic receptor (β 2 ‐ AR ) conformations that have been obtained from a set of independent molecular dynamics ( MD ) simulations in the presence of intracellular loop 3 ( ICL 3). A docking protocol was established in order to classify each receptor conformation via its binding affinity to selected ligands with known efficacy. This work's main goal was to reveal many subtle features of the ligand‐binding site, presenting alternative conformations, which might be considered as either active‐ or inactive‐like but mostly specific for that ligand. Agonists, inverse agonists, and antagonists were docked to each MD conformer with distinct binding pockets, using different docking tools and scoring functions. Mostly favored receptor conformation persistently observed in all docking/scoring evaluations was classified as active or inactive based on the type of ligand's biological effect. Classified MD conformers were further tested for their ability to discriminate agonists from inverse agonists/antagonists, and several conformers were proposed as important targets to be used in virtual screening experiments that were often limited to a single X‐ray structure.