Probing the orphan receptors: Tools and directions

Franchini, Luca; Orlandi, Cesare

doi:10.1016/bs.pmbts.2022.06.011

Cited by 7 publications

(8 citation statements)

References 114 publications

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“…It not only narrows the gap in laboratory experiments that deal with proteins but also reduces the challenges related to the structure elucidation of unknown proteins. Therefore, by implementing such advanced machine learning approaches, it is feasible to create a wide range of protein related data that can serve the purpose of sustainable protein concepts. , In this study, we employed machine learning approaches to identify potential therapeutics from the fenugreek seeds to inhibit DPP-IV enzyme.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, by implementing such advanced machine learning approaches, it is feasible to create a wide range of protein related data that can serve the purpose of sustainable protein concepts. 32,33 In this study, we employed machine learning approaches to identify potential therapeutics from the fenugreek seeds to inhibit DPP-IV enzyme.…”

Section: Drug Likeness and Molecular Dockingmentioning

confidence: 99%

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In Silico Molecular Docking and Dynamic Investigations of Bioactive Phytoconstituents from Fenugreek Seeds as a Potent Drug against DPP-IV Enzyme

Sarker,

Ray,

Rouf

et al. 2023

ACS Food Sci. Technol.

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Type 2 diabetes is a metabolic disorder resulting from impaired insulin action or dysfunction in β cells. The incretin hormone, glucagon-like peptide-1, is secreted during the meal intake, and dipeptidyl peptidase IV (DPP-IV) rapidly degrades it. The discovery of new DPP-IV inhibitors from natural resources has become an attractive approach to drug discovery. The aim of this in silico study was to identify potential therapeutic lead compounds from fenugreek (Trigonella foenum-graecum) seeds. Our molecular docking study revealed that 20 compounds out of 46 reported compounds of fenugreek seeds demonstrated high affinities (−8.8 to −4.4 kcal/mol). Further molecular dynamics (MD) simulations followed by principal component analysis showed that isovitexin and deoxyrhapontin stabilized the protein quite well and manifested stable RMSD, RMSF, Rg, and SASA profiles throughout the MD simulations. The Molecular Mechanics-Poisson−Boltzmann surface area (MMPBSA) binding free energy analysis further clarified the higher binding affinity of isovitexin compared to the control.

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Section: Resultsmentioning

confidence: 99%

Section: Drug Likeness and Molecular Dockingmentioning

confidence: 99%

In Silico Molecular Docking and Dynamic Investigations of Bioactive Phytoconstituents from Fenugreek Seeds as a Potent Drug against DPP-IV Enzyme

Sarker,

Ray,

Rouf

et al. 2023

ACS Food Sci. Technol.

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“…A number of methodological approaches have been developed and applied over the years to pair GPCRs and their ligands. This review is not intended to go into detail about these strategies which have already been described in length elsewhere (Chung et al, 2008;Fang et al, 2008;Franchini and Orlandi, 2023;Jobe and Vijayan, 2024;Satake et al, 2023;Yasi et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Deorphanization of G Protein Coupled Receptors (GPCRs): a historical perspective.

Franchini,

Orlandi

2024

Mol Pharmacol

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Counting over 800 members, G Protein Coupled Receptors (GPCRs) form the largest family of membrane receptors encoded in the human genome. Since the discovery of G proteins and GPCRs in the late 1970s and early 1980s, a significant portion of the GPCR research has been focused on identifying ligand/receptor pairs in parallel to studies related to their signaling properties. Despite significant advancements, about a fourth of the ~400 non-odorant GPCRs are still considered orphan because their natural or endogenous ligands have yet to be identified. We should consider that every GPCR was once an orphan and that endogenous ligands have often been associated with biological effects without a complete understanding of the molecular identity of their target receptors. Within this framework, this review offers a historical perspective on deorphanization processes for representative GPCRs, including Ghrelin receptor, GABAB receptor, Apelin receptor, Cannabinoid receptors, and GPR15. It explores three main scenarios encountered in deorphanization efforts and discusses key questions and methodologies employed in elucidating ligandreceptor interactions, providing insights for future research endeavors. SIGNIFICANCE STATEMENTUnderstanding how scientists have historically approached the issue of GPCR deorphanization and pairing of biologically active ligands with their cognate receptors are relevant topics in pharmacology. In fact, the biology of each GPCR, including their pathophysiological involvement, has often been uncovered only after their deorphanization, illuminating druggable targets for various diseases. Furthermore, uncovered endogenous ligands have therapeutic value as many ligands -or derivates thereof -are developed into drugs.

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“…Notably, 29% of FDA-approved drugs target these rhodopsin-like GPCRs, and approximately 500 novel GPCR drug candidates are presently undergoing clinical trials. , Despite advancements, a substantial number of rhodopsin-like receptors are categorized as “orphans”. These orphan receptors, around 120 in number, still possess mostly unknown physiological functions and lack identified endogenous ligands . As a result, our understanding of the role of orphan GPCRs (oGPCRs) in mediating signal transduction within the central nervous system (CNS) remains significantly limited.…”

Section: Introductionmentioning

confidence: 99%

“…These orphan receptors, around 120 in number, still possess mostly unknown physiological functions and lack identified endogenous ligands. 11 As a result, our understanding of the role of orphan GPCRs (oGPCRs) in mediating signal transduction within the central nervous system (CNS) remains significantly limited. However, evidence from animal studies, post-mortem transcriptomic analysis of patients, and genome-wide association studies have unveiled the critical involvement of oGPCRs in the realms of neuropharmacology and psychopharmacology.…”

Section: Introductionmentioning

confidence: 99%

Orphan G Protein-Coupled Receptor GPR37 as an Emerging Therapeutic Target

Bolinger,

Frazier,

et al. 2023

ACS Chem. Neurosci.

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G protein-coupled receptors (GPCRs) are successful druggable targets, making up around 35% of all FDA-approved medications. However, a large number of receptors remain orphaned, with no known endogenous ligand, representing a challenging but untapped area to discover new therapeutic targets. Among orphan GPCRs (oGPCRs) of interest, G protein-coupled receptor 37 (GPR37) is highly expressed in the central nervous system (CNS), particularly in the spinal cord and oligodendrocytes. While its cellular signaling mechanisms and endogenous receptor ligands remain elusive, GPR37 has been implicated in several important neurological conditions, including Parkinson's disease (PD), inflammation, pain, autism, and brain tumors. GPR37 structure, signaling, emerging physiology, and pharmacology are reviewed while integrating a discussion on potential therapeutic indications and opportunities.

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Probing the orphan receptors: Tools and directions

Cited by 7 publications

References 114 publications

In Silico Molecular Docking and Dynamic Investigations of Bioactive Phytoconstituents from Fenugreek Seeds as a Potent Drug against DPP-IV Enzyme

In Silico Molecular Docking and Dynamic Investigations of Bioactive Phytoconstituents from Fenugreek Seeds as a Potent Drug against DPP-IV Enzyme

Deorphanization of G Protein Coupled Receptors (GPCRs): a historical perspective.

Orphan G Protein-Coupled Receptor GPR37 as an Emerging Therapeutic Target

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