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Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors

The delta opioid receptor is a Gi-protein-coupled receptor (GPCR) with a broad expression pattern both in the central nervous system and the body. The receptor has been investigated as a potential target for a multitude of significant diseases including migraine, alcohol use disorder, ischemia, and...

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Autores principales: Meqbil, Yazan J., van Rijn, Richard M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324648/
https://www.ncbi.nlm.nih.gov/pubmed/35890173
http://dx.doi.org/10.3390/ph15070873
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author Meqbil, Yazan J.
van Rijn, Richard M.
author_facet Meqbil, Yazan J.
van Rijn, Richard M.
author_sort Meqbil, Yazan J.
collection PubMed
description The delta opioid receptor is a Gi-protein-coupled receptor (GPCR) with a broad expression pattern both in the central nervous system and the body. The receptor has been investigated as a potential target for a multitude of significant diseases including migraine, alcohol use disorder, ischemia, and neurodegenerative diseases. Despite multiple attempts, delta opioid receptor-selective molecules have not been translated into the clinic. Yet, the therapeutic promise of the delta opioid receptor remains and thus there is a need to identify novel delta opioid receptor ligands to be optimized and selected for clinical trials. Here, we highlight recent developments involving the delta opioid receptor, the closely related mu and kappa opioid receptors, and in the broader area of the GPCR drug discovery research. We focus on the validity and utility of the available delta opioid receptor structures. We also discuss the increased ability to perform ultra-large-scale docking studies on GPCRs, the rise in high-resolution cryo-EM structures, and the increased prevalence of machine learning and artificial intelligence in drug discovery. Overall, we pose that there are multiple opportunities to enable in silico drug discovery at the delta opioid receptor to identify novel delta opioid modulators potentially with unique pharmacological properties, such as biased signaling.
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spelling pubmed-93246482022-07-27 Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors Meqbil, Yazan J. van Rijn, Richard M. Pharmaceuticals (Basel) Review The delta opioid receptor is a Gi-protein-coupled receptor (GPCR) with a broad expression pattern both in the central nervous system and the body. The receptor has been investigated as a potential target for a multitude of significant diseases including migraine, alcohol use disorder, ischemia, and neurodegenerative diseases. Despite multiple attempts, delta opioid receptor-selective molecules have not been translated into the clinic. Yet, the therapeutic promise of the delta opioid receptor remains and thus there is a need to identify novel delta opioid receptor ligands to be optimized and selected for clinical trials. Here, we highlight recent developments involving the delta opioid receptor, the closely related mu and kappa opioid receptors, and in the broader area of the GPCR drug discovery research. We focus on the validity and utility of the available delta opioid receptor structures. We also discuss the increased ability to perform ultra-large-scale docking studies on GPCRs, the rise in high-resolution cryo-EM structures, and the increased prevalence of machine learning and artificial intelligence in drug discovery. Overall, we pose that there are multiple opportunities to enable in silico drug discovery at the delta opioid receptor to identify novel delta opioid modulators potentially with unique pharmacological properties, such as biased signaling. MDPI 2022-07-15 /pmc/articles/PMC9324648/ /pubmed/35890173 http://dx.doi.org/10.3390/ph15070873 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Meqbil, Yazan J.
van Rijn, Richard M.
Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors
title Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors
title_full Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors
title_fullStr Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors
title_full_unstemmed Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors
title_short Opportunities and Challenges for In Silico Drug Discovery at Delta Opioid Receptors
title_sort opportunities and challenges for in silico drug discovery at delta opioid receptors
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324648/
https://www.ncbi.nlm.nih.gov/pubmed/35890173
http://dx.doi.org/10.3390/ph15070873
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