Polypharmacology of Some Medicinal Plant Metabolites Against SARS-CoV-2 and Host Targets: Molecular Dynamics Evaluation of NSP9 RNA Binding Protein

Abstract

<p><b>Background: </b>Medicinal plants, as rich sources of bioactive compounds with antiviral properties, are now being explored for the development of drugs against SARS-CoV-2.</p><p><b>Aims: </b>Identification of promising compounds for the treatment of COVID-19 from natural products via molecular modelling against NSP9, including some other viral and host targets and evaluation of polypharmacological indications.</p><p><b>Main methods: </b>A manually curated library of 521 phytochemicals (from 19 medicinal plants) was virtually screened using Mcule server and binding interactions were studied using DS Visualiser. Docking thresholds were set based on the scores of standard controls and rigorous ADMET properties were used to finally get the potential inhibitors. Free binding energies of the docked complexes were calculated employing MM-GBSA method. MM-GBSA informed our choice for MD simulation studies performed against NSP9 to study the stability of the drug-receptor interaction. NSP9 structure comparison was also performed. </p><p><b>Key findings: </b>Extensive screening of the molecules identified 5 leads for NSP9, 23 for Furin, 18 for ORF3a, and 19 for interleukin-6. Ochnaflavone and Licoflavone B, obtained from Lonicera japonica (Japanese Honeysuckle) and Glycyrrhiza glabra (Licorice), respectively, were identified to have the highest potential multi-target inhibition properties for NSP9, furin, ORF3a, and IL-6. Additionally, molecular dynamics simulation supports the robust stability of Ochnaflavone and Licoflavone B against NSP9 at the active sites via hydrophobic interactions, H-bonding, and H-bonding facilitated by water.</p><b>Significance:</b> These compounds with the highest drug-like ranking against multiple viral and host targets have the potential to be drug candidates for the treatment of SARS-CoV-2 infection that may possibly act on multiple pathways simultaneously to inhibit viral entry and replication as well as disease progression.

Andrographis paniculata (Burm. f.) Wall. ex Nees: An Updated Review of Phytochemistry, Antimicrobial Pharmacology, and Clinical Safety and Efficacy

“…Therefore, searching for potential bioactive compounds from natural sources is an ongoing investigation as medicinal plants possess a tremendous antiviral compound. In recent in silico studies, andrographolide [227], neoandrographolide [228], glycosides 5,4 -dihydroxy-7-O-β-D-pyran-glycuronate butyl ester [229] and glycoside 3-O-β-D-glucopyranosyl-andrographolide [229] have been reported to have a potential role in inhibiting the main protease of SARS-CoV-2, including NSP9, RNA-dependent RNA polymerase, and 6LU7. Andrographolide was docked successfully in the binding site of SARS-CoV-2 Mpro.…”

Phytoconstituents from Markhamia tomentosa Bind To HPV Oncoprotein with Apoptogenic Potential: A Molecular Modeling Approach

“…Molecular interactions between the top screened ligands with low binding energy, good drug-likeness and ADMET properties and protein targets were analysed for receptor-ligand interactions. The non-covalent interaction including the occurrence of hydrogen bond, van der Waals, pi-pi, pi-sigma, pi-sulfur and other hydrophobic interactions of the ligand-protein complex were viewed with Chimera tool UCSF 1.14 and BIOVIA Discovery studio 2020 (Bandyopadhyay et al, 2020;Johnson et al, 2020).…”