Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

Abstract

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.

Keywords: COVID-19; anti-inflammatory compounds; coronavirus; cytokine storm; molecular docking; molecular dynamics simulation; natural products; p38 MAPK.

Figure 1

A surface representation of the structure of p38 MAPK (Chain A). The catalytic ATP binding pocket is colored green. The structure is a monomer with a binding cavity of 1365.552 ų.

Figure 2

Evaluating the performance of the virtual screening via ROC curve. Binding energies from the screening of inhibitors and decoys against the p38 MAPK receptor were used to generate the curve. An AUC of 0.704 was obtained from the ROC curve.

Figure 3

Docking poses and protein-ligand interaction studies of top four hits with the lowest binding energies (a) ZINC95486106, (b) ZINC95913720, (c) ZINC33832090, and (d) ZINC95919076 against p38 MAPK structure. The binding pockets are represented as surfaces and the ligands as sticks. In the LigPlot+ representations, the ligands are displayed as purple sticks, hydrophobic contacts are shown as red spoke arcs, and the hydrogen bonds with their respective bond lengths as green.

Figure 3

Docking poses and protein-ligand interaction studies of top four hits with the lowest binding energies (a) ZINC95486106, (b) ZINC95913720, (c) ZINC33832090, and (d) ZINC95919076 against p38 MAPK structure. The binding pockets are represented as surfaces and the ligands as sticks. In the LigPlot+ representations, the ligands are displayed as purple sticks, hydrophobic contacts are shown as red spoke arcs, and the hydrogen bonds with their respective bond lengths as green.

Figure 4

Molecular dynamics simulations graphs (a) RMSD versus time (ns) and (b) Rg versus time (ns). In (a,b), the unbound p38 MAPK protein (3ZS5), ZINC1691180, ZINC4520996, ZINC5519433, and ZINC5733756, SB 202190, and SB 203580–p38 MAPK complexes are shown as black, red, green, blue, yellow, brown, ash and purple, respectively.

Figure 4

Molecular dynamics simulations graphs (a) RMSD versus time (ns) and (b) Rg versus time (ns). In (a,b), the unbound p38 MAPK protein (3ZS5), ZINC1691180, ZINC4520996, ZINC5519433, and ZINC5733756, SB 202190, and SB 203580–p38 MAPK complexes are shown as black, red, green, blue, yellow, brown, ash and purple, respectively.

Figure 5

Snapshots at 25 ns intervals ((time step = 0, 25, 50, 75, and 100 ns) for the binding modes of the ligand-p38 MAPK complexes. The cartoon representation shows (a) ZINC1691180, (b) ZINC4520996, (c) ZINC95486106, (d) ZINC5519433 and (e) ZINC5733756- p38 MAPK complexes. The ligands are represented as spheres and the protein as cartoons. All the ligands were observed to bind stably in the ATP binding pocket.

Figure 5

Snapshots at 25 ns intervals ((time step = 0, 25, 50, 75, and 100 ns) for the binding modes of the ligand-p38 MAPK complexes. The cartoon representation shows (a) ZINC1691180, (b) ZINC4520996, (c) ZINC95486106, (d) ZINC5519433 and (e) ZINC5733756- p38 MAPK complexes. The ligands are represented as spheres and the protein as cartoons. All the ligands were observed to bind stably in the ATP binding pocket.

Figure 6

The total number of hydrogen bonds formed between the selected compounds and the protein structure. ZINC1691180, ZINC4520996, ZINC95486106, ZINC5519433, ZINC5733756, SB 202190, and SB 203580-p38 MAPK complexes are represented as black, red, green, blue, yellow, brown and ash, respectively.

Figure 7

Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) plot of binding free energy contribution per-residue of ZINC5519433-p38 MAPK complex. Fluctuations of the residues Tyr35, Val38, Ala51, Lys53, Thr106, Leu108, Met109, and Phe169 are colored red.