Molecular Docking and Pharmacokinetic Profiling of Dimethyl ellagic acid from Eucalyptus globulus as a Broad-Spectrum Inhibitor of Microbial and Insecticidal Virulence Toxins

Abstract

Background: Antimicrobial resistance and toxin-mediated virulence are significant health issues of concern worldwide. Aim: This study set out to computationally refurbish Dimethyl ellagic acid as a pan-specific toxin protein inhibitor of bacteria, insects, arachnids, and marine organisms by evaluating binding affinity and ADMET. Methods: The ligand was minimized and optimized in PDBQT format with rotatable bonds and Gasteiger charges. The toxin structures were pre-processed by using four toxins: Clostridium botulinum (3BTA), Apis mellifera (1POC), Agelenopsis aperta (1OAV), and Conus magus (1OMG) to remove the water molecules, add the polar hydrogen atoms, and Kollman charges. AutoDock Vina (v1.2.0) under a rigid receptor flexible ligand (grid box: 20x20x20A; exhaustiveness:4) was used to carry out molecular docking. The poses with the highest ranking were chosen by binding energy and orientation. Prediction of ADMET properties was done through ADMET-AI. Results: C. botulinum toxin (−7.712 kcal/mol) was found to bind with the highest affinity, with the assistance of hydrogen bonding with Ser, Thr, and Asn, and hydrophobic interactions with Leu, Ile, Val, and Ala. The affinities observed between moderate were between A. mellifera (−5.163 kcal/mol) and A. aperta (−5.158 kcal/mol), and C. magus exhibited the lowest affinity (−4.424 kcal/mol). The ADMET analysis showed that the drug possessed good drug-like properties such as moderate molecular weight, balanced lipophilicity, good intestinal absorption, and low risk of carcinogenicity, but hepatotoxicity may need to be evaluated further. Conclusion: Dimethyl ellagic acid selectively binds well-defined toxin pockets, indicating its potential as a natural anti-virulence scaffold that needs to be experimentally confirmed.