Polypharmacology of some medicinal plant metabolites against SARS-CoV-2 and host targets: Molecular dynamics evaluation of NSP9 RNA binding protein

Abstract

Background: Medicinal plants, as rich sources of bioactive compounds with antiviral properties, are now being explored for the development of drugs against SARS-CoV-2. Aims: 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. Main methods: 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. Key findings: 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. Significance: 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.

Molecular Modeling Studies of Natural Inhibitors of Androgen Signaling in Prostate Cancer

“…The MM/GBSA method is a much more precise method of calculating the free binding energies (dG) of protein-ligand complexes. 32 It’s one of the most promising methods for improving virtual screening outcomes. Just like docking scores, a negative dG value indicates that the complexes formed in the binding pocket of the target were stable.…”

Exploring the inhibitory potential of Nigella sativa against dengue virus NS2B/NS3 protease and NS5 polymerase using computational approaches

“…58 Apigenin, campesterol, cycloeucalenol, bsitosterol, dithymoquinone, stigmasterol, taraxerol, nigellidine, and nigellicine have shown signicant bioavailability (Table 3) and were found to have potential as signicant protease and enzyme inhibitors. [59][60][61] The majority of phytocomponents, including apigenin, campesterol, carvone, nigellicine, nigellidine, nigellimine, and nigelline, showed high human intestinal absorption (GI absorption), lipophilicity and blood-brain permeation, indicating high absorption and transport kinetics in the stomach and the ability to easily cross the BBB (Table 4). Toxicity risk assessment BBB (Table 5) through LD 50 value and toxicity class BBB suggests that apigenin, astragalin, taraxerol and thymoquinone are expected to be safe as they exhibited non-mutagenic, non-tumorigenic, non-carcinogenic, nonirritant behaviour with no threats to reproductive systems.…”

Bioactive Constituents of Safflower plant as potential inhibitors of mutant Leucine-rich repeat kinase 2 (LRRK2): Docking, Pharmacokinetics properties and Molecular Dynamics studies

“…Carrying out all required processes in the wet laboratory is not only time consuming but also yield an extreme cost. Therefore, pharmacokinetics prediction is a route to salvaging time, resources and cost in nding potential lead molecule as it lters possible lead compounds at a minimal cost (Bandyopadhyay et al 2021). Table 3 shows the drug likeliness and pharmacokinetics of the hit compounds.…”

“…C1B showed a stark increase in its RMSD after about 80ns and remains stable throughout the rest of the duration. This is suggested to be as a result of change in conformation (Bandyopadhyay et al 2021); however, it maintains an RMSD similar to the apoprotein indicating that the C1B complex results in a similar conformation as the native conformation (Swargiary et al 2022). The RMSD values for the ROC domain for 7LI3 complex and apo were within 1 to 5 Amstrong.…”