Network Pharmacology Reveals Cis-4-Benzyl-2,6-diphenyltetrahydropyran's
Impact on Neurotransmitter Signaling, GPCR Modulation, and Cellular
Pathways Associated with Diabetes Mellitus
Authors: Vishwanadham Rao Vyshnavi , Narayanappa Shanti Koppala 
Published: January 2025

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:
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.

Method:
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.

Result:
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.