"Multiscale computational analysis guided discovery of a multitarget antitubercular ligand from Oxalis corniculata...

The global Tuberculosis fatality ratio is around 50% for the treated cases as per WHO Global Tuberculosis Report 2025.Available antitubercular drugs have limited efficacy with the potential to cause organ toxicity. Thus, there is a need for new drug therapies to combat tuberculosis. Oxalis corniculata Linn are peculiar to the tropical and subtropic regions. They are rich in alkaloids, phenolic compounds, and glycolipids and are used to treat several diseases. Despite being widely used, the antitubercular screening was not reported.

Plant-based multi-target directed antitubercular ligand identification from O. corniculatawas carried out by successive extraction of crude plant material using different solvents.Tannins, flavonoids, polyphenols, steroids, alkaloids, volatile oils, palmitic acid, linoleic acid, linolenic acid, stearic acid, and oleic acid were the predominant phytochemicals present. The antitubercular potential of the extract was screened on the H37Rv strain by Alamar blue assay. A GC-MS spectral analysis was followed by Molecular docking,a ligand docking complex (2CIG-ET_170) was selected for molecular dynamics simulations to calculate the binding free energy over 500 ns, PCA and FEL study,along with ADMET properties were investigated with a promising moleculeET-170. The only extract Hydro-alcohol,showed equipotent antitubercular activity with one of the selected standard drug Pyrazinamide.

305 compounds wereidentified by GCMS analysis. A few compounds like WA-126, WA-138 and ET-170 (multi-target directed), and EA-43 (single-target directed). Among them, ET-170 would be a promising molecule based on the high binding energy and lower polar solvation energy with protein 2CIG than standard obtained from MD Simulations, stable conformation of 2CIG-ET_170 (ligand protein complex) from PCA and FEL study, the electronic reactivity trend from FMO and DFT Analysis, and druglikeness and synthetic accessibility.

This study supports improved tuberculosis treatment through the development of a simple, cost-effective antitubercular molecule (ET-170). In silico pharmacokinetic and pharmacodynamic predictions enhance its drug development potential, aiding formulation design, selection of route of drug administration, and toxicity assessment. Further in vitro and in vivo studies are required for clinical validation." Further study and optimisation are needed to develop novel antitubercular drugs and effective treatment strategies for tuberculosis.