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

Abstract

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.

Keywords:

• Parkia-bioactive entities
• SARS-CoV-2-receptors
• multi-target-directed-approach
• ADMET
• molecular-docking
• molecular-simulation

Acknowledgements

The authors thank Mizoram University, Aizawl, Mizoram, India for providing infrastructural facilities and administrative support to carry out this research work.

Authors’ contributions

RD, NN, CA, BR, CU, and RS carried out the investigation, data analysis, data acquisition, supervision, writing, reviewing and editing, formal analysis, and revision of the manuscript. BB, SAL, BM, RMB, GA, BP, and MK performed the data analysis, data acquisition, visualization, and formal analysis. VKR and GG conceived the concept, hypothesis, funding acquisition, designing the experiments, supervision, original draft preparation, reviewing, editing, formal analysis, visualization, and investigation. All authors read and approved the final manuscript.

Data availability statement

The authors declare that all necessary data supporting the findings of this study are available within the article.

Disclosure statement

Authors declare that there are no conflicts of interest.

Additional information

Funding

This work was supported by the instrumentation facility in the Department of Zoology, Mizoram University through the University Grants Commission (UGC STRIDE, No.F.2-2/2019 (STRIDE-I), 3 December 2019) and the Department of Science and Technology (DST-FIST, No. SR/FST/LS-I/2017/15(C), 6 September 2018), New Delhi to GG and VKR.