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In silico structure prediction, molecular docking and dynamic simulation studies on G Protein-Coupled Receptor 116: a
Indiraleka Muthiah1, Karthikeyan Rajendran1, Premnath Dhanaraj2
1Department of Biotechnology, Mepco Schlenk Engineering College, Sivakasi, India.
Abstract:
G Protein-Coupled Receptor gains more importance in cancer research; because of their key role in several physiologic functions of cells. However, most of the GPCR's are orphan receptors, this hampers the finding of drugs against GPCR. G Protein-Coupled Receptor 116 is an adhesion orphan receptor that intensifies the invasion of cells in Triple-Negative Breast Cancer. In this study, existing FDA approved anticancer drugs were chosen as ligands and molecular docking was performed using in silico protein model of GPR116. Molecular interaction was analyzed carefully to identify the crucial amino acids present in binding pocket. Molecular dynamics simulations study executed to verify the structural and dynamic properties of Doxorubicin-GPR116 protein complex. The results have shown that Doxorubicin, Neratinib maleate, Epirubicin, and Lapatinib Ditosylate have good interaction with GPR116 binding site. Tyrosine 195 (Y195), Cysteine 196 (C196), Argenine 197 (R197), and Tryptophan 100 (W100) are commonly found in the majority of ligand-target interaction, hence based on the computational studies selective amino acids might be crucial for functional properties. Further to confirm crucial amino acids, computational mutation studies were executed. Molecular docking analysis with mutated GPR116 disclosed that significant variation in G score compared withligand-native protein interaction. Hence, the theoretical confirmatory structural properties changes support to prove selective crucial amino acids play the significant role in ligand binding. Molecular dynamic simulation results reveal that the interaction was stable throughout the MD simulation. To the best of our prognosis, GPR116 could be the best molecular target for breast cancer drug discovery.Communicated by Ramaswamy H. Sarma.
Insights
G Protein-Coupled Receptor 116 (GPR116) shows potential as a drug target for Triple-Negative Breast Cancer. Computational studies identified key amino acids and confirmed stable interactions with approved anticancer drugs, suggesting GPR116 as a promising target for new therapies.
Area of Science:
- Oncology
- Pharmacology
- Computational Biology
Background:
- G Protein-Coupled Receptors (GPCRs) are crucial in cellular functions and cancer research.
- Many GPCRs are orphan receptors, posing challenges for drug development.
- G Protein-Coupled Receptor 116 (GPR116), an adhesion orphan receptor, is implicated in Triple-Negative Breast Cancer cell invasion.
Purpose of the Study:
- To investigate the potential of GPR116 as a molecular target for Triple-Negative Breast Cancer drug discovery.
- To identify FDA-approved anticancer drugs that interact with GPR116 using computational methods.
- To analyze the binding interactions and identify crucial amino acids in the GPR116 binding pocket.
Main Methods:
- *In silico* molecular docking of FDA-approved anticancer drugs against a GPR116 protein model.
- Analysis of molecular interactions to pinpoint key amino acids in the binding site.
- Molecular dynamics simulations to assess the stability of drug-GPR116 complexes.
- Computational mutation studies to validate the role of identified crucial amino acids.
Main Results:
- Doxorubicin, Neratinib maleate, Epirubicin, and Lapatinib Ditosylate demonstrated favorable interactions with the GPR116 binding site.
- Tyrosine 195, Cysteine 196, Arginine 197, and Tryptophan 100 were identified as potentially crucial amino acids for ligand binding.
- Mutation studies confirmed the significant role of these selective amino acids in ligand-target interactions.
- Molecular dynamics simulations indicated stable interactions between Doxorubicin and GPR116 throughout the simulation period.
Conclusions:
- GPR116 is a promising molecular target for developing novel therapeutic strategies against Triple-Negative Breast Cancer.
- The identified FDA-approved drugs and crucial amino acids provide a foundation for further drug discovery efforts.
- Computational approaches, including docking and molecular dynamics, are valuable tools for identifying and validating drug targets.
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