Multiform structure-based identification of natural phytochemical inhibitors targeting RAMP1 for migraine therapy

Research article | https://doi.org/10.47262/BL/12.1.20260402

Haleema Bibi¹*, Aliza Maryam², Atika Azhar¹, Laraib Nawaz¹

¹Department of Genomics and Bioinformatics, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan

²Department of Bioinformatics, The Islamia University of Bahawalpur, Bahawalpur, Pakistan

Abstract

Migraine is a prevalent neurological disorder primarily driven by activation of calcitonin gene-related peptide (CGRP) receptor system, in which receptor activity modifying protein 1 (RAMP1) plays a critical structural and functional role in stabilizing CGRP receptor complex. In this analysis, an in-silico drug designing approach was utilized for the identification of naturally existing phytochemicals that have strong inhibitory activity against RAMP-1. In present study, an in-silico drug discovery approach was employed to identify naturally occurring phytochemicals with potential inhibitory activity against RAMP1. The three-dimensional structure of RAMP1 was retrieved and prepared for molecular docking analysis, while twenty-five phytochemicals with reported anti-inflammatory properties were selected as candidate ligands. Molecular docking was performed to evaluate the binding affinity and protein-ligand interactions. Ursonic acid exhibited highest binding affinity (-7.8kcal/mol), followed by rutin (-7.1 kcal/mol) and β-sitosterol (-7.0 kcal/mol). Interaction analysis of the docked complexes identified 36 unique amino acid residues involved in ligand binding with Tyr-66, Trp-84, Pro85, Val-89, Asp-90, Phe-93 and His-97. ADMET analysis revealed that 23 of the 25 compounds compiled with Lipinski’s Rule of Five. By integrating molecular docking with pharmacokinetics and toxicity predictions, ursonic acid and β-sitosterol were identified as the most significant phytochemical candidates for further analysis as potential RAMP1 target as anti-migraine agent.