Exploring the Antifibrotic Potential of Vitex negundo Compounds via Molecular Docking, Molecular Dynamics and ADMET Profiling: An In-silico Analysis

Introduction: Fibrosis is the excessive accumulation of extracellular matrix in tissues due to abnormal wound healing, leading to organ dysfunction and high morbidity and mortality across multiple organs. Vitex negundo L. (Verbenaceae), commonly known as the Chinese chaste tree or "Huangjing," is an aromatic shrub native to South and Southeast Asia, China, Japan, and East Africa. It is widely recognised in traditional medicine systems for its diverse pharmacological actions. The plant exhibits anti-inflammatory, antioxidant, antifibrotic, hepatoprotective, and antimicrobial properties. These effects are primarily attributed to its rich phytochemical constituents, such as luteolin, casticin, and negundoside. Owing to its multifaceted bioactivity, Vitex negundo serves as a promising source for the development of novel therapeutic agents. Aim: To evaluate the antifibrotic potential of Vitex negundo bioactive compounds through in-silico methods, including molecular docking, molecular dynamics, and ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) profile analysis, focusing on their interaction with key fibrotic signaling pathways. Materials and Methods: This in-silico analysis was conducted in the Department of Pharmacology, Sri Ramachandra Medical College, Chennai, Tamil Nadu, India, over a period of one month, from June 2025 to July 2025. The study focused on the molecular docking of casticin, luteolin, and negundoside with TGFβR1 and SMAD3. Optimised ligand and protein structures were sourced from public databases, and ADMET properties were predicted using SWISSADME and ProTox 3.0. Molecular docking (AutoDock Vina) and visualisation (PyMOL) were used to assess binding, while 100 ns molecular dynamics simulations (AMBER ff19SB) evaluated complex stability using Root Mean Square Deviation (RMSD), Principal Component Analysis (PCA), and Molecular Mechanics/Generalised Born Surface Area (MM/ GBSA) binding energy calculations. Results: Casticin, luteolin, and negundoside from Vitex negundo showed strong binding to TGFβR1 and moderate to strong binding to SMAD3, with casticin having the highest affinities. Molecular dynamics confirmed stable, rigid proteinligand complexes for casticin and luteolin. ADMET analysis indicated high gastrointestinal absorption and low toxicity for all three compounds; however, casticin and luteolin may cause drug-drug interactions due to Cytochrome P450 (CYP) inhibition, while negundoside showed lower absorption but minimal metabolic risk. Conclusion: Vitex negundo demonstrates significant antiinflammatory, antioxidant, and antifibrotic activities. These findings support its potential as a safe and effective therapeutic agent with anti-inflammatory properties, justifying further investigation into its antifibrotic activity