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- ISSN: 1875-6921
- E-ISSN: 1875-6913
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Network Pharmacology Reveals Cis-4-Benzyl-2,6-diphenyltetrahydropyran's Impact on Neurotransmitter Signaling, GPCR Modulation, and Cellular Pathways Associated with Diabetes Mellitus
- Source: Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics), Volume 22, Issue 1, Jan 2025, E18756921350095
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- 05 Sep 2024
- 05 Dec 2024
- 24 Jan 2025
Abstract
Aims
To investigate the pharmacological implications of the ligand cis-4-Benzyl-2,6-diphenyltetrahydropyran, focusing on its pathways, potential disease associations, and therapeutic applications in Type 2 Diabetes Mellitus (T2DM).
Background/Introduction
Cis-4-Benzyl-2,6-diphenyltetrahydropyran has been previously identified for its heightened binding affinity to T2DM targets. Understanding its diverse pathways and interactions with neurotransmitter signaling, neuronal receptors, and enzymes/metabolism can provide insights into its potential roles in disease modulation and therapeutic applications.
Objectives
The primary objective of this study was to investigate the pharmacological effects of cis-4-Benzyl-2,6-diphenyltetrahydropyran in the context of Type 2 Diabetes Mellitus (T2DM). The study sought to understand its influence on neurotransmitter signaling, focusing on its modulation of G Protein-Coupled Receptors (GPCRs) and their role in diabetes pathogenesis. Utilizing KEGG pathway and gene ontology analyses, the study aimed to explore the ligand's involvement in neuroactive ligand-receptor interactions and the calcium signaling pathway, examining its broader impact on biological functions like inflammation, immune response, reproductive processes, and cellular metabolism associated with diabetes.
Methods
The study employed KEGG pathway and gene ontology analyses to profile cis-4-Benzyl-2,6-diphenyltetrahydropyran. The ligand's influence on neurotransmitter signaling, neuronal receptors, enzymes, and metabolic pathways was examined. Enrichment analysis was conducted to identify associated genes and pathways, focusing on the ligand's role in Neuroactive ligand-receptor interaction and the Calcium signaling pathway. Molecular docking and molecular dynamic simulations were performed to assess the ligand's interaction with the OPRK1 receptor, a G protein-coupled receptor implicated in metabolic regulation. Binding stability was analyzed using Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (Rg), and Solvent Accessible Surface Area (SASA). MMPBSA binding free energy analysis was conducted to validate the stability and strength of the ligand-receptor interaction.
Results and Discussion
The study revealed that cis-4-Benzyl-2,6-diphenyltetrahydropyran significantly impacts neurotransmitter signaling and cellular homeostasis by modulating GPCR pathways, including neuroactive ligand-receptor interaction and calcium signaling pathways. These pathways play critical roles in inflammation, immune response, reproductive processes, and cellular metabolism. Molecular docking and dynamic simulations demonstrated a strong and stable binding between the ligand and the OPRK1 receptor, a key GPCR implicated in metabolic regulation. The binding was supported by favorable binding free energy values (-255.58 kJ/mol) and consistent structural stability metrics, including minimal deviations in RMSD (0.2–0.4 nm) and stable radius of gyration (2.35–2.45 nm). Solvent Accessible Surface Area (SASA) analysis confirmed a compact ligand-receptor interaction, while hydrogen bonding reinforced binding specificity. These findings highlight the ligand's relevance in diabetes pathogenesis, particularly in regulating pathways involved in insulin sensitivity and glucose metabolism.
Conclusion
This study advances our understanding of the cellular effects of cis-4-Benzyl-2,6-diphenyltetrahydropyran, highlighting its multifaceted potential in diabetes research. The strong interaction with OPRK1 suggests that the ligand could influence key pathways related to insulin sensitivity and metabolic regulation. However, the findings are derived from computational methodologies, and experimental validation through in vitro and in vivo studies is essential to confirm the ligand's biological activity and therapeutic relevance. The findings establish a foundation for targeted investigations and drug development, positioning this ligand as a promising candidate for therapeutic applications in diabetes mellitus.
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