scholarly journals Pan-Cancer Analysis and Drug Formulation for GPR139 and GPR142

2021 ◽  
Vol 11 ◽  
Author(s):  
Aman Chandra Kaushik ◽  
Aamir Mehmood ◽  
Xiaofeng Dai ◽  
Dong-Qing Wei
Keyword(s):  
G Protein ◽  
Strong Association ◽  
3D Qsar ◽  
Quantitative Structure Activity Relationship ◽  
Drug Formulation ◽  
Genomic Alteration ◽  
Protein Receptor ◽  
3D Database ◽  
G Protein Coupled ◽  
Pan Cancer

GPR (G protein receptor) 139 and 142 are novel foundling GPCRs (G protein-coupled receptors) in the class “A” of the GPCRs family and are suitable targets for various biological conditions. To engage these targets, validated pharmacophores and 3D QSAR (Quantitative structure-activity relationship) models are widely used because of their direct fingerprinting capability of the target and an overall accuracy. The current work initially analyzes GPR139 and GPR142 for its genomic alteration via tumor samples. Next to that, the pharmacophore is developed to scan the 3D database for such compounds that can lead to potential agonists. As a result, several compounds have been considered, showing satisfactory performance and a strong association with the target. Additionally, it is gripping to know that the obtained compounds were observed to be responsible for triggering pan-cancer. This suggests the possible role of novel GPR139 and GPR142 as the substances for initiating a physiological response to handle the condition incurred as a result of cancer.

Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT1A and 5-HT7 G protein-coupled receptor affinity, 3D-QSAR and molecular modeling

2020 ◽  
Vol 28 (3) ◽  
pp. 115262 ◽  
Author(s):  
Charles K. Perry ◽  
Austen B. Casey ◽  
Daniel E. Felsing ◽  
Rajender Vemula ◽  
Mehreen Zaka ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
G Protein ◽  
3D Qsar ◽  
G Protein Coupled Receptor ◽  
Receptor Affinity ◽  
G Protein Coupled

scholarly journals Modelo molecular teórico del receptor serotoninérgico 5HT2A acoplado a proteína G

2012 ◽  
Vol 17 (2) ◽  
pp. 119
Author(s):  
Rafael Eduardo Malagón Bernal ◽  
Manuel Alejandro Fernández Navas ◽  
Orlando Emilio Acevedo Sarmiento
Keyword(s):  
Theoretical Model ◽  
G Protein ◽  
Tertiary Structure ◽  
Homo Sapiens ◽  
Molecular Model ◽  
Ramachandran Plot ◽  
Bovine Rhodopsin ◽  
Protein Receptor ◽  
G Protein Coupled ◽  
Hydrophobicity Profile

<strong>Objective</strong> Build a theoretical molecular model of the tertiary structure of the Homo sapiens 5HT2A receptor from experimentally obtained structures as templates. <strong>Materials</strong> <strong>and methods</strong> In the construction of the theoretical model we considered the protocol established by Ballesteros and Weinstein for the construction of the G-protein coupled receptor, by the alignment of the amino acid sequence, hydrophobicity profiles, refinement of loops by spatial restrictions and energy minimization with the force field OPLS_2005. <strong>Results</strong> The resulting model was validated by the Ramachandran plot with 91.7% of amino acids within the limits set for angles phi and psi and a RMSD of 0.95 Å with respect to bovine rhodopsin. <strong>Conclusions</strong> We obtained a validated theoretical model useful in studies of ligand-receptor docking.<br /><strong>Key words</strong>: G protein receptor, hydrophobicity profile, Ramachandran plot, orthosteric site, molecular modelling.

scholarly journals Pan-cancer in silico analysis of somatic mutations in G-protein coupled receptors: The effect of evolutionary conservation and natural variance

2021 ◽  
Author(s):  
Brandon J Bongers ◽  
Marina Gorostiola González ◽  
Xuesong Wang ◽  
Herman WT van Vlijmen ◽  
Willem Jespers ◽  
...  
Keyword(s):  
G Protein ◽  
Structural Integrity ◽  
In Silico Analysis ◽  
G Protein Coupled Receptors ◽  
Dry Motif ◽  
Synthetic Ligand ◽  
Natural Variance ◽  
G Protein Coupled ◽  
Pan Cancer

G protein-coupled receptors (GPCRs) form the most frequently exploited drug target family, moreover they are often found mutated in cancer. Here we used an aggregated dataset of mutations found in cancer patient samples derived from the Genomic Data Commons and compared it to the natural human variance as exemplified by data from the 1000 Genomes project. While the location of these mutations across the protein domains did not differ significantly in the two datasets, a mutation enrichment was observed in cancer patients among conserved residues in GPCRs such as the 'DRY' motif. We subsequently created a ranking of high scoring GPCRs, using a multi-objective approach (Pareto Front Ranking). The validity of our approach was confirmed by re-discovery of established cancer targets such as the LPA and mGlu receptor families, and we identified novel GPCRs that had not been directly linked to cancer before such as the P2Y Receptor 10 (P2RY10). As a proof of concept, we projected the structurally investigated mutations in the crystal structure of the C-C Chemokine (CCR) 5 receptor, one of the high-ranking GPCRs previously linked to cancer. Several positions were pinpointed that relate to either structural integrity or endogenous and synthetic ligand binding, providing a rationale to their mechanism of influence in cancer. In conclusion, this study identifies a list of GPCRs that are prioritized for experimental follow up characterization to elucidate their role in cancer. The computational approach here described can be adapted to investigate the roles in cancer of any protein family.

A Pan-Cancer Analysis of the Oncogenic Role of G Protein-Coupled Bile Acid Receptor 1(GPBAR1) in Human Tumors

2021 ◽  
Author(s):  
Zhiyuan Guan ◽  
Xiao Jin ◽  
Shengfu Liu ◽  
Zhong Wu ◽  
Ruijun Cong ◽  
...  
Keyword(s):  
Bile Acid ◽  
G Protein ◽  
Human Tumors ◽  
Acid Receptor ◽  
Bile Acid Receptor ◽  
G Protein Coupled ◽  
Pan Cancer

scholarly journals An Integrated Pan-Cancer Analysis and Structure-Based Virtual Screening of GPR15

2019 ◽  
Vol 20 (24) ◽  
pp. 6226 ◽  
Author(s):  
Yanjing Wang ◽  
Xiangeng Wang ◽  
Yi Xiong ◽  
Cheng-Dong Li ◽  
Qin Xu ◽  
...  
Keyword(s):  
Virtual Screening ◽  
G Protein ◽  
Large Scale ◽  
3D Structure ◽  
Rectal Adenocarcinoma ◽  
Squamous Carcinoma ◽  
The Cancer Genome Atlas ◽  
G Protein Coupled ◽  
Pan Cancer

G protein-coupled receptor 15 (GPR15, also known as BOB) is an extensively studied orphan G protein-coupled receptors (GPCRs) involving human immunodeficiency virus (HIV) infection, colonic inflammation, and smoking-related diseases. Recently, GPR15 was deorphanized and its corresponding natural ligand demonstrated an ability to inhibit cancer cell growth. However, no study reported the potential role of GPR15 in a pan-cancer manner. Using large-scale publicly available data from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases, we found that GPR15 expression is significantly lower in colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) than in normal tissues. Among 33 cancer types, GPR15 expression was significantly positively correlated with the prognoses of COAD, neck squamous carcinoma (HNSC), and lung adenocarcinoma (LUAD) and significantly negatively correlated with stomach adenocarcinoma (STAD). This study also revealed that commonly upregulated gene sets in the high GPR15 expression group (stratified via median) of COAD, HNSC, LUAD, and STAD are enriched in immune systems, indicating that GPR15 might be considered as a potential target for cancer immunotherapy. Furthermore, we modelled the 3D structure of GPR15 and conducted structure-based virtual screening. The top eight hit compounds were screened and then subjected to molecular dynamics (MD) simulation for stability analysis. Our study provides novel insights into the role of GPR15 in a pan-cancer manner and discovered a potential hit compound for GPR15 antagonists.

scholarly journals Desensitization of the Neurokinin-1 Receptor (NK1-R) in Neurons: Effects of Substance P on the Distribution of NK1-R, Gαq/11, G-Protein Receptor Kinase-2/3, and β-Arrestin-1/2

1998 ◽  
Vol 9 (8) ◽  
pp. 2305-2324 ◽  
Author(s):  
Karen McConalogue ◽  
Carlos U. Corvera ◽  
Patrick D. Gamp ◽  
Eileen F. Grady ◽  
Nigel W. Bunnett
Keyword(s):  
Plasma Membrane ◽  
Substance P ◽  
G Protein ◽  
Neurokinin 1 Receptor ◽  
Protein Receptor ◽  
Early Endosomes ◽  
Receptor Kinases ◽  
Neurokinin 1 ◽  
G Protein Coupled ◽  
Neurotransmitter Substance

Observations in reconstituted systems and transfected cells indicate that G-protein receptor kinases (GRKs) and β-arrestins mediate desensitization and endocytosis of G-protein–coupled receptors. Little is known about receptor regulation in neurons. Therefore, we examined the effects of the neurotransmitter substance P (SP) on desensitization of the neurokinin-1 receptor (NK1-R) and on the subcellular distribution of NK1-R, Gαq/11, GRK-2 and -3, and β-arrestin-1 and -2 in cultured myenteric neurons. NK1-R was coexpressed with immunoreactive Gαq/11, GRK-2 and -3, and β-arrestin-1 and -2 in a subpopulation of neurons. SP caused 1) rapid NK1-R–mediated increase in [Ca2+]i, which was transient and desensitized to repeated stimulation; 2) internalization of the NK1-R into early endosomes containing SP; and 3) rapid and transient redistribution of β-arrestin-1 and -2 from the cytosol to the plasma membrane, followed by a striking redistribution of β-arrestin-1 and -2 to endosomes containing the NK1-R and SP. In SP-treated neurons Gαq/11 remained at the plasma membrane, and GRK-2 and -3 remained in centrally located and superficial vesicles. Thus, SP induces desensitization and endocytosis of the NK1-R in neurons that may be mediated by GRK-2 and -3 and β-arrestin-1 and -2. This regulation will determine whether NK1-R–expressing neurons participate in functionally important reflexes.

scholarly journals Improved Antibacterial Host Defense and Altered Peripheral Granulocyte Homeostasis in Mice Lacking the Adhesion Class G Protein Receptor CD97

2006 ◽  
Vol 75 (3) ◽  
pp. 1144-1153 ◽  
Author(s):  
Tao Wang ◽  
Linhua Tian ◽  
Makoto Haino ◽  
Ji-Liang Gao ◽  
Ross Lake ◽  
...  
Keyword(s):  
Bone Marrow ◽  
G Protein ◽  
Dermatan Sulfate ◽  
Systemic Infection ◽  
Cell Types ◽  
Wild Type ◽  
Protein Receptor ◽  
Alternatively Spliced ◽  
The Difference ◽  
G Protein Coupled

ABSTRACT CD97 is a member of the adhesion family of G protein-coupled receptors. Alternatively spliced forms of CD97 bind integrins α5β1 and αvβ3, decay accelerating factor, or dermatan sulfate. CD97 is expressed on myeloid cells at high levels and a variety of other cell types at lower levels. Little is known about the physiological function of CD97. To begin dissecting the function of CD97, we evaluated the immune response of CD97 null mice to systemic infection by Listeria monocytogenes. CD97 null mice were significantly more resistant to listeriosis than matched wild-type mice. A major determinant of the difference in survival appeared to be the comparatively more robust accumulation of granulocytes in the blood and in infected livers of CD97 null mice within 18 h of inoculation, correlating with a decrease in the number of bacteria. CD97 null mice also displayed a mild granulocytosis in the nonchallenged state. Because there is a strong suggestion that CD97 functions in an adhesive capacity, we examined the migratory properties of granulocytes in CD97 null mice. In chimeric animals, CD97 null and wild-type granulocytes migrated similarly, as determined by inflammation-induced emigration from the bone marrow and accumulation in the peritoneum. Granulocyte development in the bone marrow of CD97 null mice was comparable to that of wild-type mice, and CD97 deficiency did not appear to stimulate granulocytosis secondary to peripheral inflammation and resultant granulocyte colony-stimulating factor induction, unlike various other models of adhesion deficiencies. Our results suggest that CD97 plays a role in peripheral granulocyte homeostasis.

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