In silico Assessment of Efficacy Against the Zoonotic Parasite Echinococcus granulosus, Pharmacokinetic and Toxicity Predictions for the Siddha Formulation Murukkanvithai Mathirai

Abstract

Background: Thioredoxin glutathione reductase (TGR) is essential for survival of the zoonotic tapeworm Echinococcus granulosus. Albendazole is the only promising drug for the treatment of cystic echinococcosis. To avoid the development of resistance to albendazole in the parasite, an herbal alternative to albendazole is the need-of-the-hour to combat the development of resistance. Aim: This study aimed to identify active compounds against the parasite Echinococcus granulosus from Murukkan Vithai Mathirai, an anthelmintic formulation used in Siddha practice. Objectives: To evaluate the efficacy of Murukkan Vithai Mathirai (MVM), a Siddha formulation against Echinococcus granulosus, a tapeworm of carnivores, by molecular docking, and to evaluate its ADMET properties using in silico tools. Materials and Methods: The 3D structure of Echinococcus granulosus-thioredoxin-glutathione systems (egTGR) and the phytoconstituents of Piper nigrum, Zingiber officinalis, Piper longum, Cuminum syminum, Coptis teeta, Butea monosperma, and Croton tiglium were obtained from a curated database of Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT). 12 promising phytocompounds were selected based on their physicochemical properties, drug-likeness, bioavailability scores, and medicinal chemistry properties. These phytochemicals were docked individually with the egTGR using Autodock vina and binding affinity (kcal/mol) was recorded for each compound and compared with albendazole, a positive control drug. The results of docking were read using the Biovia Discovery studio visualizer. The ADMET properties of the phytochemicals were analysed using pkCSM and VEGA-QSAR tools. The toxicity score for each phytochemical was calculated by assigning weightage to the toxicities predicted and the weighted average was calculated to compare with the albendazole's weighted average. The geometric mean of NOAELs predicted for MVM phytochemicals was compared with the predicted NOAEL of albendazole. Results: The binding affinity (G) scores of the selected phytocompounds were found to be higher than the albendazole and the phytocompounds with G > -8.0 are as follows, aristolodione, berberastine and pluviatilol of Piper longum, apigenin of Cuminum syminum and prunetin of Butea monosperma, whereas the G of albendazole was -6.7. The calculated toxicity score for MVM (0.56) was significantly lower than albendazole (1.08) and the predicted NOAELs was significantly higher (26.63 mg/kg) than albendazole (3.49), indicating that MVM is less toxic than albendazole. Conclusion: Murukkan Vithai Mathirai is a promising and safe anthelmintic in in silico studies, however, it needs to be validated by in vitro and in vivo studies.