MOLECULAR DOCKING AND COMPUTATIONAL INVESTIGATION OF MENTHA ROYLEANA PHYTOCHEMICALS TARGETING PROTEINS AND PATHWAYS INVOLVED IN GASTROINTESTINAL MOTILITY

Abstract

Gastrointestinal motility disorders are linked with deregulated smooth muscle contraction controlled by important protein targets L-type voltage-gated calcium channel Cav1.2 and M3 muscarinic acetylcholine receptor. The current study focused on an integrated in silico approach to analyze the therapeutic potential of phytocompounds of Mentha royleana against these target proteins. A total of 20 compounds, identified by GCMS technique, were subjected to QSAR analysis, drug-likeness and toxicity filters, molecular docking, and density functional theory (DFT) analysis. The best performing QSAR model,among the used multiple machine learning algorithms, was found to be XGBoost which enabled effective prioritization of compounds based on predicted inhibitory activity (pIC50). Preliminary drug-likeness evaluation by Lipinski and Veber rules and safety screening helped in further prioritization of compounds. Molecular docking study revealed compound 1-[alpha-(1-Adamantyl)benzylidene]thiosemicarbazide (CPD1) having strong binding affinity scores(up to -9.7 kcal/mol) with both targets, supported by hydrogen and hydrophobic interactions. DFT technique provided understandings about electronic properties of ligands, with lowest HOMO-LUMO energy gap (4.719 eV) and highest dipole moment (5.943 D) was found for CPD1, supporting its higher reactivity and binding affinity. Drug-likeness analysis indicated favorable oral absorption while pharmacokinetic profiling exhibited acceptable ADMET properties for most lead compounds, though some compounds with predicted toxicity require optimization. Overall, the study emphasizes compound CPD1 as a promising lead drug candidate demonstrating a balance of predicted biological activity, binding interactions, and electronic stability. The study results have revealed that M. royleana is a beneficial source of bioactive phytocompounds with potential antispasmodic effect by dual inhibition of M3R receptor and Cav1.2 channel. This in silico framework demonstrates the pharmacological relevance of M. royleana and delivers a strong basis for further experimental validation of predicted findings and rational drug development for targeting gastrointestinal motility disorders.