Abstract
Drug development is an arduous procedure, necessitating testing the interaction of a large number of potential candidates with potential interacting (macro)molecules. Therefore, any method which could provide an initial screening of potential candidate drugs might be of interest for the acceleration of the procedure, by highlighting interesting compounds, prior to in vitro and in vivo validation. In this line, we present a method which may identify potential hits, with agonistic and/or antagonistic properties on GPCR receptors, integrating the knowledge on signaling events triggered by receptor activation (GPCRs binding to Gα,β,γ proteins, and activating Gα, exchanging GDP for GTP, leading to a decreased affinity of the Gα for the GPCR). We show that, by integrating GPCR‐ligand and Gα‐GDP or ‐GTP binding in docking simulation, which correctly predicts crystallographic data, we can discriminate agonists, partial agonists, and antagonists, through a linear function, based on the ΔG (Gibbs‐free energy) of liganded‐GPCR/Gα‐GDP. We built our model using two Gαs (β2‐adrenergic and prostaglandin‐D2), four Gαi (μ‐opioid, dopamine‐D3, adenosine‐A1, rhodopsin), and one Gαo (serotonin) receptors and validated it with a series of ligands on a recently deorphanized Gαi receptor (OXER1). This approach could be a valuable tool for initial in silico validation and design of GPRC‐interacting ligands.
Highlights
IntroductionProgress in biochemistry and cell biology resulted in a better understanding of the events and necessary steps involved in the interaction of a cell with an administered drug substance, leading to the discovery and/or synthesis of novel pharmaceuticals
G-protein-coupled receptors (GPCR) are involved in different signal transduction pathways, triggered by a plurality of extracellular signals (including photons, light-sensitive compounds, photons, odorants, pheromones, hormones, neurotransmitters, and a number of ligands, varying in size from small molecules to peptides to large proteins)
We show that it can correctly predict small ligand putative agonistic or antagonistic nature, presenting a valuable tool that could significantly accelerate the search of novel molecules in GPCR pharmacology
Summary
Progress in biochemistry and cell biology resulted in a better understanding of the events and necessary steps involved in the interaction of a cell with an administered drug substance, leading to the discovery and/or synthesis of novel pharmaceuticals. Membrane receptors can be distinguished as onepass single-chain proteins, acting as mono- or oligomers and multiple passes proteins. Among the latter, the seven transmembrane helix (7TM) GPCR family contains ~800 members overall (of which ~400 are olfactory receptors). GPCR-initiated signal transduction results in many physiological processes, interfering with the (patho)physiology of many systems, such as the endocrine (including the reproductive), neurological or cardiovascular systems. Such a wide impact, makes GPCR a preferential drug target candidate group.[2-4]. Only a small fraction of GPCRs (206 entries according to https://gpcrdb.org/ structure/statistics) have been crystallized to date, making difficult the prediction of novel pharmacological substances
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