Analysis of L-DOPA and droxidopa binding to human β 2 -adrenergic receptor

Over the last two decades, an increasing number of studies has been devoted to a deeper understanding of the molecular process involved in the binding of various agonists and antagonists to active and inactive conformations of β -adrenergic receptor (β AR). The 3.2 Å x-ray crystal structure of human...

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Bibliographic Details
Published in:Biophysical journal 2021-12, Vol.120 (24), p.5631
Main Authors: Biswas, Akash Deep, Catte, Andrea, Mancini, Giordano, Barone, Vincenzo
Format: Article
Language:English
Subjects:
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-2 Receptor Antagonists
Binding Sites
Droxidopa
Humans
Levodopa
Ligands
Molecular Docking Simulation
Receptors, Adrenergic, beta-2 - metabolism
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Summary:Over the last two decades, an increasing number of studies has been devoted to a deeper understanding of the molecular process involved in the binding of various agonists and antagonists to active and inactive conformations of β -adrenergic receptor (β AR). The 3.2 Å x-ray crystal structure of human β AR active state in combination with the endogenous low affinity agonist adrenaline offers an ideal starting structure for studying the binding of various catecholamines to adrenergic receptors. We show that molecular docking of levodopa (L-DOPA) and droxidopa into rigid and flexible β AR models leads for both ligands to binding anchor sites comparable to those experimentally reported for adrenaline, namely D113/N312 and S203/S204/S207 side chains. Both ligands have a hydrogen bond network that is extremely similar to those of noradrenaline and dopamine. Interestingly, redocking neutral and protonated versions of adrenaline to rigid and flexible β AR models results in binding poses that are more energetically stable and distinct from the x-ray crystal structure. Similarly, lowest energy conformations of noradrenaline and dopamine generated by docking into flexible β AR models had binding free energies lower than those of best poses in rigid receptor models. Furthermore, our findings show that L-DOPA and droxidopa molecules have binding affinities comparable to those predicted for adrenaline, noradrenaline, and dopamine, which are consistent with previous experimental and computational findings and supported by the molecular dynamics simulations of β AR-ligand complexes performed here.
ISSN:1542-0086