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

被引:6
|
作者
Meqbil, Yazan J. [1 ]
van Rijn, Richard M. [2 ,3 ]
机构
[1] Purdue Univ, Dept Med Chem & Mol Pharmacol, Computat Interdisciplinary Grad Program, W Lafayette, IN 47907 USA
[2] Purdue Univ, Purdue Inst Drug Discovery, Purdue Inst Neurosci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA
[3] Septerna Inc, San Francisco, CA 94080 USA
关键词
mutagenesis; artificial intelligence; computer-aided drug design; molecular dynamic simulation; biased signaling; G protein-coupled receptor; POSITIVE ALLOSTERIC MODULATORS; MOLECULAR PHARMACOLOGY; RESPIRATORY DEPRESSION; GENETIC-VARIATION; SINGLE RESIDUE; HIGH-AFFINITY; AGONIST; BINDING; LIGAND; ACTIVATION;
D O I
10.3390/ph15070873
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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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页数:15
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