Discovery of Potential SARS-CoV-2 Papain-like Protease Natural Inhibitors Employing a Multi-Phase In Silico Approach

Abstract

As an extension of our research against COVID-19, a multiphase in silico approach was applied in the selection of the three most common inhibitors (Glycyrrhizoflavone (76), Arctigenin (94), and Thiangazole (298)) against papain-like protease, PLpro (PDB ID: 4OW0), among 310 metabolites of natural origin. All compounds of the exam set were reported as antivirals. The structural similarity between the examined compound set and S88, the co-crystallized ligand of PLpro, was examined through structural similarity and fingerprint studies. The two experiments pointed to Brevicollin (28), Cryptopleurine (41), Columbamine (46), Palmatine (47), Glycyrrhizoflavone (76), Licochalcone A (87), Arctigenin (94), Termilignan (98), Anolignan B (99), 4,5-dihydroxy-6″-deoxybromotopsentin (192), Dercitin (193), Tryptanthrin (200), 6-Cyano-5-methoxy-12-methylindolo [2, 3A] carbazole (211), Thiangazole (298), and Phenoxan (300). The binding ability against PLpro was screened through molecular docking, disclosing the favorable binding modes of six metabolites. ADMET studies expected molecules 28, 76, 94, 200, and 298 as the most favorable metabolites. Then, molecules 76, 94, and 298 were chosen through in silico toxicity studies. Finally, DFT studies were carried out on glycyrrhizoflavone (76) and indicated a high level of similarity in the molecular orbital analysis. The obtained data can be used in further in vitro and in vivo studies to examine and confirm the inhibitory effect of the filtered metabolites against PLpro and SARS-CoV-2.

Keywords: ADMET; DFT; SARS-CoV-2; molecular docking; natural products; papain-like protease; structural similarity.

Figure 5

(A) Three-dimensional and (B) two-dimensional binding modes of S88 in the active site of PLpro. As shown in Figure 6, compound 76 expressed a ΔG of −51.63 into the PLpro active site. Compound 76 made four HBs with Tyr265, Thr302, Tyr274, and Gln270. Moreover, the aromatic systems were included in many HIs with Asp165, Pro249, Tyr265, Gly164, Leu163, and Tyr269.

Figure 5

(A) Three-dimensional and (B) two-dimensional binding modes of S88 in the active site of PLpro. As shown in Figure 6, compound 76 expressed a ΔG of −51.63 into the PLpro active site. Compound 76 made four HBs with Tyr265, Thr302, Tyr274, and Gln270. Moreover, the aromatic systems were included in many HIs with Asp165, Pro249, Tyr265, Gly164, Leu163, and Tyr269.

Figure 1

In silico protocol to select the most promising candidate against PLpro.

Figure 2

Thirty molecules with good molecular similarity with S88.

Figure 3

The similarity outputs of the tested compounds and S88. Green balls = S88, red balls = similar molecules, blue balls = not similar molecules. (A) First 50 molecules, (B) second 50 molecules, (C) third 50 molecules, (D) fourth 50 molecules, (E) fifth 50 molecules, and (F) last 60 molecules.

Figure 4

Superimposition of the co-crystallized pose (magenta) and the re-docking pose (turquoise) of the same ligand (S88) in the active site of the PLpro enzyme.

Figure 6

(A) Three-dimensional and (B) two-dimensional binding modes of compound 76 in the PLpro active site.

Figure 6

(A) Three-dimensional and (B) two-dimensional binding modes of compound 76 in the PLpro active site.

Figure 7

(A) Three-dimensional and (B) two-dimensional binding modes of compound 94 in the PLpro active site.

Figure 7

(A) Three-dimensional and (B) two-dimensional binding modes of compound 94 in the PLpro active site.

Figure 8

(A) Three-dimensional and (B) two-dimensional binding modes of compound 98 in the PLpro active site.

Figure 8

(A) Three-dimensional and (B) two-dimensional binding modes of compound 98 in the PLpro active site.

Figure 9

(A) Three-dimensional and (B) two-dimensional binding modes of compound 193 in the PLpro active site.

Figure 9

(A) Three-dimensional and (B) two-dimensional binding modes of compound 193 in the PLpro active site.

Figure 10

(A) Three-dimensional and (B) two-dimensional binding modes of compound 200 in the PLpro active site.

Figure 10

(A) Three-dimensional and (B) two-dimensional binding modes of compound 200 in the PLpro active site.

Figure 11

(A) Three-dimensional and (B) two-dimensional binding modes of compound 298 in the PLpro active site.

Figure 11

(A) Three-dimensional and (B) two-dimensional binding modes of compound 298 in the PLpro active site.

Figure 12

The expected ADMET characters.

Figure 13

Molecular orbitals spatial distribution for (A) S88, (B) 76, (C) 94, and (D) 298.

Figure 14

Molecular electrostatic potential map of (A) S88, (B) 76, (C) 94, and (D) 298.