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Network Biology, 2026, 16(3): 103-116
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Article

Deciphering Metabolite-MRGPRD interactions: A computational insight into RAS pathway modulation

Neelam Krishna, Shraddha Vishwakarma, Pramod Katara
Centre of Bioinformatics, IIDS, University of Allahabad, Prayagraj-21002, UP, India

Received 20 November 2025;Accepted 30 December 2025;Published online 3 January 2026;Published 1 September 2026
IAEES

Abstract
The renin-angiotensin system (RAS) regulates diverse physiological processes, making it a highly complex and tightly controlled biological network. RAS components signal through two major pathways that mediate both proliferative and anti-proliferative effects. Dysregulation of this system has been implicated in cardiovascular and renal disorders, as well as in SARS-CoV-2 infection. Mas-related G protein-coupled receptor member D (MRGPRD), an emerging RAS-associated protein, has been linked to multiple physiological conditions, including cancer progression and blood pressure regulation. Lacto-tripeptides - bioactive peptides derived from milk - are known modulators of ACE activity and can influence RAS-mediated blood pressure control. In this study, structure-based virtual screening was performed using 206 cow-milk metabolites docked against the MRGPRD receptor. The top-ranked metabolite-protein complex was further examined using molecular dynamics simulations (150 ns) to assess interaction stability and structural dynamics. Among the screened metabolites, BMDB0012305 demonstrated the highest binding affinity and is reported to possess inhibitory potential toward MRGPRD. Molecular dynamics analyses (RMSD, RMSF, and Rg) revealed that the "MRGPRD-BMDB0012305"complex remained stable throughout the simulation, supported by persistent intermolecular interactions such as hydrogen bonding. Overall, our findings suggest that the milk-derived metabolite BMDB0012305 may interact with and modulate MRGPRD function, potentially influencing downstream RAS-related physiological processes. This highlights the need for further experimental validation to understand its biological impact and potential role in RAS-associated abnormalities.

Keywords renin angiotensin;MRGPRD;molecular docking;milk metabolites;MD simulation.


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