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

• Published in: Life (Basel, Switzerland) Switzerland), 2022-09, Vol.12 (9), p.1407
• Main Authors: Elkaeed, Eslam B, Metwaly, Ahmed M, Alesawy, Mohamed S, Saleh, Abdulrahman M, Alsfouk, Aisha A, Eissa, Ibrahim H
• Format: Article
• Language: English
• Subjects: ADMET; Antiviral agents; Binding; Binding sites; Biocompatibility; Carbazole; Carbazoles; Chemistry; Coronaviruses; COVID-19; Crystallization; In vivo methods and tests; Inhibitors; Licochalcone A; Ligands; Metabolites; Molecular docking; Molecular orbitals; Multiphase; Natural products; Papain; papain-like protease; Protease; Protease inhibitors; Proteinase; Proteinase inhibitors; Proteins; SARS-CoV-2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Similarity; Software; structural similarity; Toxicity
• ISSN: 2075-1729; 2075-1729
• DOI: 10.3390/life12091407

As an extension of our research against COVID-19, a multiphase approach was applied in the selection of the three most common inhibitors (Glycyrrhizoflavone ( ), Arctigenin ( ) and Thiangazole ( )) 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 , the co-crystallized ligand of PLpro, was examined through structural similarity and fingerprint studies. The two experiments pointed to Brevicollin ( ), Cryptopleurine ( ), Columbamine ( ), Palmatine ( ), Glycyrrhizoflavone ( ), Licochalcone A ( ), Arctigenin ( ), Termilignan ( ), Anolignan B ( ), 4,5-dihydroxy-6″-deoxybromotopsentin ( ), Dercitin ( ), Tryptanthrin ( ), 6-Cyano-5-methoxy-12-methylindolo [2, 3A] carbazole ( ), Thiangazole ( ), and Phenoxan ( ). The binding ability against PLpro was screened through molecular docking, disclosing the favorable binding modes of six metabolites. ADMET studies expected molecules , , , , and as the most favorable metabolites. Then, molecules , , and were chosen through toxicity studies. Finally, DFT studies were carried out on glycyrrhizoflavone ( ) and indicated a high level of similarity in the molecular orbital analysis. The obtained data can be used in further and studies to examine and confirm the inhibitory effect of the filtered metabolites against PLpro and SARS-CoV-2.