A simple open source bioinformatic methodology for initial exploration of GPCR ligands’ agonistic/antagonistic properties
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 acc...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-08-01
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| Series: | Pharmacology Research & Perspectives |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/prp2.600 |
| _version_ | 1819094410456989696 |
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| author | Athanasios A. Panagiotopoulos Christina Papachristofi Konstantina Kalyvianaki Panagiotis Malamos Panayiotis A. Theodoropoulos George Notas Theodora Calogeropoulou Elias Castanas Marilena Kampa |
| author_facet | Athanasios A. Panagiotopoulos Christina Papachristofi Konstantina Kalyvianaki Panagiotis Malamos Panayiotis A. Theodoropoulos George Notas Theodora Calogeropoulou Elias Castanas Marilena Kampa |
| author_sort | Athanasios A. Panagiotopoulos |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T23:26:58Z |
| format | Article |
| id | doaj.art-99d9f73eb16f43f5b9928baeb503cb61 |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-12-21T23:26:58Z |
| publishDate | 2020-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-99d9f73eb16f43f5b9928baeb503cb612022-12-21T18:46:36ZengWileyPharmacology Research & Perspectives2052-17072020-08-0184n/an/a10.1002/prp2.600A simple open source bioinformatic methodology for initial exploration of GPCR ligands’ agonistic/antagonistic propertiesAthanasios A. Panagiotopoulos0Christina Papachristofi1Konstantina Kalyvianaki2Panagiotis Malamos3Panayiotis A. Theodoropoulos4George Notas5Theodora Calogeropoulou6Elias Castanas7Marilena Kampa8Laboratory of Experimental Endocrinology School of Medicine University of Crete Heraklion GreeceLaboratory of Experimental Endocrinology School of Medicine University of Crete Heraklion GreeceLaboratory of Experimental Endocrinology School of Medicine University of Crete Heraklion GreeceLaboratory of Experimental Endocrinology School of Medicine University of Crete Heraklion GreeceLaboratory of Biochemistry School of Medicine University of Crete Heraklion GreeceLaboratory of Experimental Endocrinology School of Medicine University of Crete Heraklion GreeceInstitute of Chemical Biology National Hellenic Research Foundation Athens GreeceLaboratory of Experimental Endocrinology School of Medicine University of Crete Heraklion GreeceLaboratory of Experimental Endocrinology School of Medicine University of Crete Heraklion GreeceAbstract 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.https://doi.org/10.1002/prp2.600agonistantagonistbiological activity predictiondockingGPCRin silico |
| spellingShingle | Athanasios A. Panagiotopoulos Christina Papachristofi Konstantina Kalyvianaki Panagiotis Malamos Panayiotis A. Theodoropoulos George Notas Theodora Calogeropoulou Elias Castanas Marilena Kampa A simple open source bioinformatic methodology for initial exploration of GPCR ligands’ agonistic/antagonistic properties Pharmacology Research & Perspectives agonist antagonist biological activity prediction docking GPCR in silico |
| title | A simple open source bioinformatic methodology for initial exploration of GPCR ligands’ agonistic/antagonistic properties |
| title_full | A simple open source bioinformatic methodology for initial exploration of GPCR ligands’ agonistic/antagonistic properties |
| title_fullStr | A simple open source bioinformatic methodology for initial exploration of GPCR ligands’ agonistic/antagonistic properties |
| title_full_unstemmed | A simple open source bioinformatic methodology for initial exploration of GPCR ligands’ agonistic/antagonistic properties |
| title_short | A simple open source bioinformatic methodology for initial exploration of GPCR ligands’ agonistic/antagonistic properties |
| title_sort | simple open source bioinformatic methodology for initial exploration of gpcr ligands agonistic antagonistic properties |
| topic | agonist antagonist biological activity prediction docking GPCR in silico |
| url | https://doi.org/10.1002/prp2.600 |
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