Tackling the complexities of orphan GPCR ligand discovery with rationally assisted approaches

So, Sean S.; Ngo, Tony; Keov, Peter; Smith, Nicola J.; Kufareva, Irina

doi:10.1016/b978-0-12-816228-6.00016-7

Cited by 4 publications

(5 citation statements)

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“…Over 100 of the ∼800 known human G protein-coupled receptors (GPCRs) ( Fredriksson et al, 2003 ) lack a pairing to an endogenous ligand and are collectively known as ‘orphan’ receptors ( Davenport et al, 2013 ). Orphan GPCRs remain largely understudied ( So et al, 2020 ), owing mainly to the paucity of pharmacological tools available to probe receptor signaling. Many orphan receptors lack an adequate signaling assay, which is a significant roadblock to ligand discovery, and a further hindrance to identification of the physiological role of these orphan GPCRs in health and disease.…”

Section: Introductionmentioning

confidence: 99%

Deletion of Orphan G Protein-Coupled Receptor GPR37L1 in Mice Alters Cardiovascular Homeostasis in a Sex-Specific Manner

et al. 2021

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GPR37L1 is a family A orphan G protein-coupled receptor (GPCR) with a putative role in blood pressure regulation and cardioprotection. In mice, genetic ablation of Gpr37l1 causes sex-dependent effects; female mice lacking Gpr37l1 (GPR37L1−/−) have a modest but significant elevation in blood pressure, while male GPR37L1−/− mice are more susceptible to cardiovascular dysfunction following angiotensin II-induced hypertension. Given that this receptor is highly expressed in the brain, we hypothesize that the cardiovascular phenotype of GPR37L1−/− mice is due to changes in autonomic regulation of blood pressure and heart rate. To investigate this, radiotelemetry was employed to characterize baseline cardiovascular variables in GPR37L1−/− mice of both sexes compared to wildtype controls, followed by power spectral analysis to quantify short-term fluctuations in blood pressure and heart rate attributable to alterations in autonomic homeostatic mechanisms. Additionally, pharmacological ganglionic blockade was performed to determine vasomotor tone, and environmental stress tests were used to assess whether cardiovascular reactivity was altered in GPR37L1−/− mice. We observed that mean arterial pressure was significantly lower in female GPR37L1−/− mice compared to wildtype counterparts, but was unchanged in male GPR37L1−/− mice. GPR37L1−/− genotype had a statistically significant positive chronotropic effect on heart rate across both sexes when analyzed by two-way ANOVA. Power spectral analysis of these data revealed a reduction in power in the heart rate spectrum between 0.5 and 3 Hz in female GPR37L1−/− mice during the diurnal active period, which indicates that GPR37L1−/− mice may have impaired cardiac vagal drive. GPR37L1−/− mice of both sexes also exhibited attenuated depressor responses to ganglionic blockade with pentolinium, indicating that GPR37L1 is involved in maintaining sympathetic vasomotor tone. Interestingly, when these mice were subjected to aversive and appetitive behavioral stressors, the female GPR37L1−/− mice exhibited an attenuation of cardiovascular reactivity to aversive, but not appetitive, environmental stimuli. Together, these results suggest that loss of GPR37L1 affects autonomic maintenance of blood pressure, giving rise to sex-specific cardiovascular changes in GPR37L1−/− mice.

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Section: Introductionmentioning

confidence: 99%

Deletion of Orphan G Protein-Coupled Receptor GPR37L1 in Mice Alters Cardiovascular Homeostasis in a Sex-Specific Manner

et al. 2021

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“…Furthermore, 2 additional subsets of the merged active prediction set were created that individually represented predictions made for ligands complexed with experimentally determined protein structures or predictions made for ligands complexes with modeled protein structures. For each set or subset of predictions, performance of the classifier was assessed with the precision (Equation (3)), accuracy (Equation ( 4)), and recall (Equation ( 5 (5) where TP, TN, FP, and FN are the numbers of true positives, true negatives, false positives, and false negatives, respectively, for each class of ligand activity. In addition, hit rates were calculated for the merged active prediction sets using Equation (1).…”

Section: Random Forest Classifier Developmentmentioning

confidence: 99%

“…However, FDAapproved drugs only target 108 of the 360 known "druggable" non-olfactory GPCRs [4], indicating that a substantial swath of GPCR targets are yet to be clinically leveraged. Furthermore, ~25% of GPCR are still classified as "orphans", signaling that they lack a known endogenous ligand and often possess an ambiguous or undefined physiological role [5]. For these understudied GPCRs, the ability to better understand and modulate their physiological roles may illuminate poorly characterized pathways relevant to the development, progression, and treatment of disease.…”

Section: Introductionmentioning

confidence: 99%

G Protein-Coupled Receptor–Ligand Pose and Functional Class Prediction

Szwabowski,

Griffing,

Mugabe

et al. 2024

IJMS

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G protein-coupled receptor (GPCR) transmembrane protein family members play essential roles in physiology. Numerous pharmaceuticals target GPCRs, and many drug discovery programs utilize virtual screening (VS) against GPCR targets. Improvements in the accuracy of predicting new molecules that bind to and either activate or inhibit GPCR function would accelerate such drug discovery programs. This work addresses two significant research questions. First, do ligand interaction fingerprints provide a substantial advantage over automated methods of binding site selection for classical docking? Second, can the functional status of prospective screening candidates be predicted from ligand interaction fingerprints using a random forest classifier? Ligand interaction fingerprints were found to offer modest advantages in sampling accurate poses, but no substantial advantage in the final set of top-ranked poses after scoring, and, thus, were not used in the generation of the ligand–receptor complexes used to train and test the random forest classifier. A binary classifier which treated agonists, antagonists, and inverse agonists as active and all other ligands as inactive proved highly effective in ligand function prediction in an external test set of GPR31 and TAAR2 candidate ligands with a hit rate of 82.6% actual actives within the set of predicted actives.

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“…For example, phenotypic or second messenger amplification assays with the read-out many steps removed from receptor activation are vulnerable to non-specific signal interference, as was the case for p426-r37L1 1,4 , or to interference from the endogenous receptor context 6,7 . These are common challenges for orphan research 16,17 , which nevertheless should not deter us from continuing to define the pharmacology and physiology of GPR37L1 . Examination of constitutive and ligand-induced cAMP elevation in HEK293 cells transfected with or without the corrected pcDNA3.1-GPR37L1, using (a) CRE-luc or (b) CAMYEL assays.…”

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confidence: 99%

Orphan G protein-coupled receptor, GPR37L1: pharmacological toolbox empty once again

Ngo

Wilkins

et al. 2020

Preprint

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Orphan G protein-coupled receptors (GPCRs) are largely intractable therapeutic targets, owing to the lack of chemical tools for exploring their pharmacology. The discovery of such tools, however, is hampered by a number of unknowns, such as effector coupling and appropriate positive controls. In our 2017 Nature Chemical Biology paper1, we developed a computational chemical tool discovery approach called GPCR Contact-Informed Neighboring Pocket (GPCR-CoINPocket). This method predicted pharmacological similarity of GPCRs in a ligand- and structure-independent manner, to enable the discovery of off-target activities of known compounds at orphan GPCRs and hence the identification of so-called surrogate ligands. Our orphan GPCR target for prospective surrogate ligand discovery efforts was GPR37L1, a brain-specific receptor linked to cerebellar development2 and seizures3. We had previously demonstrated that GPR37L1 constitutively coupled to Gαs and generated ligand-independent increases in intracellular cAMP4§. Thus, the inverse agonist activities of computationally predicted surrogates were tested in the cAMP response element luciferase (CRE-luc) reporter gene assay in human embryonic kidney (HEK293) cells expressing either vector control or what we thought was untagged GPR37L1 in pcDNA3.1. However, we recently discovered that the GPR37L1 construct used in that study was incorrect: instead of pcDNA3.1, it carried the receptor inserted backwards into a yeast p426GPD vector (hereafter referred to as p426-r37L1). Here, we correct the cloning error and describe our subsequent unsuccessful efforts to re-test the computationally predicted GPR37L1 ligands (triggering an author-initiated retraction of1).NoteWe, the authors, are working with the Nature Chemical Biology Editors to retract our 2017 paper ‘Orphan receptor ligand discovery by pickpocketing pharmacological neighbors’1. The present manuscript is under review at Nature Chemical Biology as a Matters Arising accompaniment to the anticipated author-initiated retraction. We initiated the steps towards the retraction upon discovering a regrettable cloning error that put into question the in vitro findings reported in1. This action was unanimously agreed upon by all authors. The computational aspects of the original manuscript1 are unaffected by this error.

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Tackling the complexities of orphan GPCR ligand discovery with rationally assisted approaches

Cited by 4 publications

References 385 publications

Deletion of Orphan G Protein-Coupled Receptor GPR37L1 in Mice Alters Cardiovascular Homeostasis in a Sex-Specific Manner

Deletion of Orphan G Protein-Coupled Receptor GPR37L1 in Mice Alters Cardiovascular Homeostasis in a Sex-Specific Manner

G Protein-Coupled Receptor–Ligand Pose and Functional Class Prediction

Orphan G protein-coupled receptor, GPR37L1: pharmacological toolbox empty once again

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