Repurposing immune boosting and anti-viral efficacy of Parkia bioactive entities as multi-target directed therapeutic approach for SARS-CoV-2: exploration of lead drugs by drug likeness, molecular docking and molecular dynamics simulation methods.

The COVID-19 pandemic has caused adverse health (severe respiratory, enteric and systemic infections) and environmental impacts that have threatened public health and the economy worldwide. Drug repurposing and small molecule multi-target directed herbal medicine therapeutic approaches are the most appropriate exploration strategies for SARS-CoV-2 drug discovery. This study identified potential multi-target-directed Parkia bioactive entities against SARS-CoV-2 receptors (S-protein, ACE2, TMPRSS2, RBD/ACE2, RdRp, MPro, and PLPro) using ADMET, drug-likeness, molecular docking (AutoDock, FireDock and HDOCK), molecular dynamics simulation and MM-PBSA tools. One thousand Parkia bioactive entities were screened out by virtual screening and forty-five bioactive phytomolecules were selected based on favorable binding affinity and acceptable pharmacokinetic and pharmacodynamics properties. The binding affinity values of Parkia phyto-ligands (AutoDock: -6.00--10.40 kcal/mol; FireDock: -31.00--62.02 kcal/mol; and HDOCK: -150.0--294.93 kcal/mol) were observed to be higher than the reference antiviral drugs (AutoDock: -5.90--9.10 kcal/mol; FireDock: -35.64--59.35 kcal/mol; and HDOCK: -132.82--211.87 kcal/mol), suggesting a potent modulatory action of Parkia bioactive entities against the SARS-CoV-2. Didymin, rutin, epigallocatechin gallate, epicatechin-3-0-gallate, hyperin, ursolic acid, lupeol, stigmasta-5,24(28)-diene-3-ol, ellagic acid, apigenin, stigmasterol, and campesterol strongly bound with the multiple targets of the SARS-CoV-2 receptors, inhibiting viral entry, attachment, binding, replication, transcription, maturation, packaging and spread. Furthermore, ACE2, TMPRSS2, and MPro receptors possess significant molecular dynamic properties, including stability, compactness, flexibility and total binding energy. Residues GLU-589, and LEU-95 of ACE2, GLN-350, HIS-186, and ASP-257 of TMPRSS2, and GLU-14, MET-49, and GLN-189 of MPro receptors contributed to the formation of hydrogen bonds and binding interactions, playing vital roles in inhibiting the activity of the receptors. Promising results were achieved by developing multi-targeted antiviral Parkia bioactive entities as lead and prospective candidates under a small molecule strategy against SARS-CoV-2 pathogenesis. The antiviral activity of Parkia bioactive entities needs to be further validated by pre-clinical and clinical trials.

Dietary phytoestrogen diosgenin interrupts metabolism, physiology, and reproduction of Swiss albino mice: Possible mode of action as an emerging environmental contaminant, endocrine disruptor and reproductive toxicant.

Dietary phytoestrogens are the main source of environmental contamination due to their estrogen-mimicking and endocrine-disrupting effects, posing a threat to microbial, soil, plant, and animal health. Diosgenin, a phytosteroid saponin, is used in many traditional medicines, nutraceuticals, dietary supplements, contraceptives, and hormone replacement therapies against numerous diseases and disorders. It is important to be aware of the potential risks associated with diosgenin, as well as its potential to cause reproductive and endocrine toxicity. Due to the lack of research on the safety and probable adverse side effects of diosgenin, this work evaluated the endocrine-disrupting and reproductive toxicity of diosgenin in albino mice by following acute toxicity (OECD-423), repeated dose 90-day oral toxicity (OECD-468), and F1 extended one-generation reproductive toxicity (OECD-443) studies. Diosgenin was found to be slightly toxic, with LD50 for male and female mice being 546.26 and 538.72 mg/kg, respectively. Chronic exposure of diosgenin (10, 50, 100, and 200 mg/kg) generated oxidative stress, depleted antioxidant enzymes, disturbed homeostasis of the reproductive hormones, and interrupted steroidogenesis, germ cell apoptosis, gametogenesis, sperm quality, estrous cycle, and reproductive performance in the F0 and F1 offspring. Long-term oral exposure of diosgenin to the mice disturbed the endocrine and reproductive functions and generated transgenerational reproductive toxic effects in F0 and F1 offspring. These results suggest that diosgenin should be used carefully in food products and medical applications due to its potential endocrine-disrupting and reproductive toxic effects. The findings of this study provide a better understanding of the potential adverse effects of diosgenin and the need for appropriate risk assessment and management of its use.