African derived phytocompounds may interfere with SARS-CoV-2 RNA capping machinery via inhibition of 2'-O-ribose methyltransferase: An in silico perspective

Abstract

Despite the ongoing vaccination against the life-threatening COVID-19, there is need for viable therapeutic interventions. The S-adenosyl-l-Methionine (SAM) dependent 2-O'-ribose methyltransferase (2'-O-MTase) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a therapeutic target against COVID-19 infection. In a bid to profile bioactive principles from natural sources, a custom-made library of 226 phytochemicals from African medicinal plants with especially anti-malarial activity was screened for direct interactions with SARS-CoV-2 2'-O-MTase (S2RMT) using molecular docking and molecular dynamics (MD) simulations as well as binding free energies methods. Based on minimal binding energy lower than sinefungin (a reference methyl-transferase inhibitor) and binding mode analysis at the catalytic site of S2RMT, a list of 26 hit phytocompounds was defined. The interaction of these phytocompounds was compared with the 2'-O-MTase of SARS-CoV and MERS-CoV. Among these compounds, the lead phytocompounds (LPs) viz: mulberrofuran F, 24-methylene cycloartenol, ferulate, 3-benzoylhosloppone and 10-hydroxyusambarensine interacted strongly with the conserved KDKE tetrad within the substrate binding pocket of the 2'-O-MTase of the coronavirus strains which is critical for substrate binding. The thermodynamic parameters analyzed from the MD simulation trajectories of the LPs-S2RMT complexes presented an eminent structural stability and compactness. These LPs demonstrated favorable druggability and in silico ADMET properties over a diverse array of molecular computing descriptors. The LPs show promising prospects in the disruption of S2RMT capping machinery in silico. However, these LPs should be validated via in vitro and in vivo experimental models.

Keywords: 2-O’-ribosemethyltransferase; Coronavirus; Molecular docking; Molecular dynamics; Mulberrofuran F; Phytochemicals; SARS-CoV-2.

Graphical abstract

Fig. 1

Binding energies of the ten lead phytocompounds from the docking analysis of 226 phytocompounds and reference compounds docked to the active site of coronaviruses 2-O-methyltransferase. The red dotted line shows the top 4 docked compounds. 168 = 2, 3, 19 -trihydroxy-urs-12–20-en-28-oic acid.

Fig. 2

Amino acid interactions of top lead phytocompounds from the docking analysis and reference inhibitors in substrate binding cavity SARS-CoV-2 2′-O-MTase. (S) solvent-accessible surface view. The top four ranked phytocompounds in sticks representation are represented by colors: (a) cyan: sinefungin (b) orange: SAM (c) gold: mulberrofuran F (d) red: 24-methylene cycloartenol ferulate (e) blue: 10–hydroxyusambarensine (f) Green: 3-benzoylhosloppone. Types of interactions are represented by light purple-dotted line: Green-dotted lines: H-bonds; hydrophobic interactions (Pi-Alkyl, Alkyl and pi-stacking); yellow-dotted lines: purple-dotted line: Pi-Pi T Shaped; Pi-sulfur interactions, pi-stacking interactions, with three-letter abbreviations of amino acids.

Fig. 3

Amino acid interactions of phytocompounds and reference inhibitors in substrate binding cavity SARS-CoV 2′-O-MTase. (S) solvent-accessible surface view. The top four ranked phytocompounds in sticks representation are represented by colors: (a) cyan: sinefungin (b) orange: SAM (III) gold: mulberrofuran F (d) red: 24-methylene cycloartenol ferulate (e) blue: 10–Hydroxyusambarensine (f) Green: 3-benzoylhosloppone.

Fig. 4

Amino acid interactions of phytocompounds lead phytocompounds from the docking analysis and reference inhibitors in substrate binding cavity MERS-CoV2’-O-MTase. (S) solvent-accessible surface view. The top four ranked phytocompounds in sticks representation are represented by colors: (a) cyan: sinefungin (b) orange: SAM (c) gold: mulberrofuran F (d) red: 24-methylene cycloartenol ferulate (e) blue: 10–hydroxyusambarensine (f) green: 3-benzoylhosloppone.

Fig. 5

Secondary structural analysis of SARS-Cov-2 2′-O-MTase during 100 ns MD simulation (a) SSE distribution by residue (b) summary of the SSE composition for each trajectory frame (c) residue and its SSE assignment over time.

Fig. 6

The Backbone-Root Mean Square Deviation (RMSD) plots of molecular dynamics (MD) simulation of SARS-Cov-2 2′-O-MTase complexed to the four lead phytochemicals from the docking analysis.

Fig. 7

Per residue Root Mean Square Fluctuations (RMSF) plots of molecular dynamics (MD) simulation of SARS-Cov-2 2′-O-MTase complexed to the four lead phytochemicals from the docking analysis.

Fig. 8

The Radius of gyration (RoG) plots of molecular dynamics (MD) simulation of SARS-Cov-2 2′-O-MTase complexed to the four lead phytochemicals from the docking analysis.

Fig. 9

The Surface Accessible Surface Area (SASA) plots of molecular dynamics (MD) simulation of SARS-Cov-2 2′-O-MTase complexed to the four lead phytochemicals from the docking analysis.

Fig. 10

The changes in the number of H-bonds during the MDS trajectory of SARS-Cov-2 2′-O-MTase complexed to the four lead phytochemicals from the docking analysis.

Fig. 11

(a) A schematic details of binding groups of mulberrofuran F interacting with the amino acid residues of SARS-Cov-2 2′-O-MTase (S2RMT) during the period of 100 ns MD simulation analysis. Interactions that occured more than 30.0% of the simulation time in the selected trajectory (0.00 through 100.00 ns), are shown (b) simulation interactions plot showing categorized S2RMT- mulberrofuran F interactions.

Fig. 12

(a)A schematic details of binding groups of 24-Methylene cycloartenol ferulate interacting with the amino acid residues of SARS-Cov-2 2′-O-MTase (S2RMT) during the period of 100 ns MD simulation analysis. Interactions that occured more than 30.0% of the simulation time in the selected trajectory (0.00 through 100.00 ns) are shown (b) simulation interactions plot showing categorized S2RMT- 24-Methylene cycloartenol ferulate interactions.

Fig. 13

(a) A schematic details of binding groups of 10 -Hydroxyusambarensine interacting with the amino acid residues of SARS-Cov-2 2′-O-MTase (S2RMT) during the period of 100 ns MD simulation analysis. Interactions that occurred more than 30.0% of the simulation time in the selected trajectory (0.00 through 100.00 ns) are shown (b) simulation interactions plot showing categorized S2RMT-10 -Hydroxyusambarensine interactions.

Fig. 14

(a) A schematic details of binding groups of 3-Benzoylhosloppone interacting with the amino acid residues of SARS-Cov-2 2′-O-MTase (S2RMT) during the period of 100 ns MD simulation analysis. Interactions that occurred more than 30.0% of the simulation time in the selected trajectory (0.00 through 100.00 ns) are shown (b) simulation interactions plot showing categorized S2RMT-3-Benzoylhosloppone interactions.

Fig. 15

Free energy landscape (FEL) between first and second principal components (PC1, PC2) graph representation for SARS-Cov-2 2′-O-MTase complexed with (a) mulberrofuran F (b) 24-methylene cycloartenol ferulate (c) 10 –hydroxyusambarensine (d) 3- benzoylhosloppone and (e) without any compound systems.