Discovery of C-12 dithiocarbamate andrographolide analogues as inhibitors of SARS-CoV-2 main protease: In vitro and in silico studies
A global crisis of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has impacted millions of people’s lives throughout the world. In parallel to vaccine development, identifying potential antiviral agents against SARS-CoV-2 has becom...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-01-01
|
| Series: | Computational and Structural Biotechnology Journal |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037022002094 |
| _version_ | 1797978223009595392 |
|---|---|
| author | Bodee Nutho Patcharin Wilasluck Peerapon Deetanya Kittikhun Wangkanont Patcharee Arsakhant Rungnapha Saeeng Thanyada Rungrotmongkol |
| author_facet | Bodee Nutho Patcharin Wilasluck Peerapon Deetanya Kittikhun Wangkanont Patcharee Arsakhant Rungnapha Saeeng Thanyada Rungrotmongkol |
| author_sort | Bodee Nutho |
| collection | DOAJ |
| description | A global crisis of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has impacted millions of people’s lives throughout the world. In parallel to vaccine development, identifying potential antiviral agents against SARS-CoV-2 has become an urgent need to combat COVID-19. One of the most attractive drug targets for discovering anti-SARS-CoV-2 agents is the main protease (Mpro), which plays a pivotal role in the viral life cycle. This study aimed to elucidate a series of twenty-one 12-dithiocarbamate-14-deoxyandrographolide analogues as SARS-CoV-2 Mpro inhibitors using in vitro and in silico studies. These compounds were initially screened for the inhibitory activity toward SARS-CoV-2 Mpro by in vitro enzyme-based assay. We found that compounds 3k, 3l, 3m and 3t showed promising inhibitory activity against SARS-CoV-2 Mpro with >50% inhibition at 10 μM. Afterward, the binding mode of each compound in the active site of SARS-CoV-2 Mpro was explored by molecular docking. The optimum docked complexes were then chosen and subjected to molecular dynamic (MD) simulations. The MD results suggested that all studied complexes were stable along the simulation time, and most of the compounds could fit well with the SARS-CoV-2 Mpro active site, particularly at S1, S2 and S4 subsites. The per-residue decomposition free energy calculations indicated that the hot-spot residues essential for ligand binding were T25, H41, C44, S46, M49, C145, H163, M165, E166, L167, D187, R188, Q189 and T190. Therefore, the obtained information from the combined experimental and computational techniques could lead to further optimization of more specific and potent andrographolide analogues toward SARS-CoV-2 Mpro. |
| first_indexed | 2024-04-11T05:19:33Z |
| format | Article |
| id | doaj.art-72d2447e5e7f41e99357e0809f252094 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-11T05:19:33Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-72d2447e5e7f41e99357e0809f2520942022-12-24T04:52:46ZengElsevierComputational and Structural Biotechnology Journal2001-03702022-01-012027842797Discovery of C-12 dithiocarbamate andrographolide analogues as inhibitors of SARS-CoV-2 main protease: In vitro and in silico studiesBodee Nutho0Patcharin Wilasluck1Peerapon Deetanya2Kittikhun Wangkanont3Patcharee Arsakhant4Rungnapha Saeeng5Thanyada Rungrotmongkol6Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Corresponding author.Center of Excellence for Molecular Biology and Genomics of Shrimp, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; Molecular Crop Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, ThailandCenter of Excellence for Molecular Biology and Genomics of Shrimp, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; Molecular Crop Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, ThailandCenter of Excellence for Molecular Biology and Genomics of Shrimp, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; Molecular Crop Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, ThailandDepartment of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand; The Research Unit in Synthetic Compounds and Synthetic Analogues from Natural Product for Drug Discovery (RSND), Burapha University, Chonburi 20131, ThailandDepartment of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand; The Research Unit in Synthetic Compounds and Synthetic Analogues from Natural Product for Drug Discovery (RSND), Burapha University, Chonburi 20131, ThailandCenter of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, ThailandA global crisis of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has impacted millions of people’s lives throughout the world. In parallel to vaccine development, identifying potential antiviral agents against SARS-CoV-2 has become an urgent need to combat COVID-19. One of the most attractive drug targets for discovering anti-SARS-CoV-2 agents is the main protease (Mpro), which plays a pivotal role in the viral life cycle. This study aimed to elucidate a series of twenty-one 12-dithiocarbamate-14-deoxyandrographolide analogues as SARS-CoV-2 Mpro inhibitors using in vitro and in silico studies. These compounds were initially screened for the inhibitory activity toward SARS-CoV-2 Mpro by in vitro enzyme-based assay. We found that compounds 3k, 3l, 3m and 3t showed promising inhibitory activity against SARS-CoV-2 Mpro with >50% inhibition at 10 μM. Afterward, the binding mode of each compound in the active site of SARS-CoV-2 Mpro was explored by molecular docking. The optimum docked complexes were then chosen and subjected to molecular dynamic (MD) simulations. The MD results suggested that all studied complexes were stable along the simulation time, and most of the compounds could fit well with the SARS-CoV-2 Mpro active site, particularly at S1, S2 and S4 subsites. The per-residue decomposition free energy calculations indicated that the hot-spot residues essential for ligand binding were T25, H41, C44, S46, M49, C145, H163, M165, E166, L167, D187, R188, Q189 and T190. Therefore, the obtained information from the combined experimental and computational techniques could lead to further optimization of more specific and potent andrographolide analogues toward SARS-CoV-2 Mpro.http://www.sciencedirect.com/science/article/pii/S2001037022002094COVID-19SARS-CoV-2 main proteaseAndrographolide analoguesMolecular dockingMD simulationsEnzyme-based assay |
| spellingShingle | Bodee Nutho Patcharin Wilasluck Peerapon Deetanya Kittikhun Wangkanont Patcharee Arsakhant Rungnapha Saeeng Thanyada Rungrotmongkol Discovery of C-12 dithiocarbamate andrographolide analogues as inhibitors of SARS-CoV-2 main protease: In vitro and in silico studies Computational and Structural Biotechnology Journal COVID-19 SARS-CoV-2 main protease Andrographolide analogues Molecular docking MD simulations Enzyme-based assay |
| title | Discovery of C-12 dithiocarbamate andrographolide analogues as inhibitors of SARS-CoV-2 main protease: In vitro and in silico studies |
| title_full | Discovery of C-12 dithiocarbamate andrographolide analogues as inhibitors of SARS-CoV-2 main protease: In vitro and in silico studies |
| title_fullStr | Discovery of C-12 dithiocarbamate andrographolide analogues as inhibitors of SARS-CoV-2 main protease: In vitro and in silico studies |
| title_full_unstemmed | Discovery of C-12 dithiocarbamate andrographolide analogues as inhibitors of SARS-CoV-2 main protease: In vitro and in silico studies |
| title_short | Discovery of C-12 dithiocarbamate andrographolide analogues as inhibitors of SARS-CoV-2 main protease: In vitro and in silico studies |
| title_sort | discovery of c 12 dithiocarbamate andrographolide analogues as inhibitors of sars cov 2 main protease in vitro and in silico studies |
| topic | COVID-19 SARS-CoV-2 main protease Andrographolide analogues Molecular docking MD simulations Enzyme-based assay |
| url | http://www.sciencedirect.com/science/article/pii/S2001037022002094 |
| work_keys_str_mv | AT bodeenutho discoveryofc12dithiocarbamateandrographolideanaloguesasinhibitorsofsarscov2mainproteaseinvitroandinsilicostudies AT patcharinwilasluck discoveryofc12dithiocarbamateandrographolideanaloguesasinhibitorsofsarscov2mainproteaseinvitroandinsilicostudies AT peerapondeetanya discoveryofc12dithiocarbamateandrographolideanaloguesasinhibitorsofsarscov2mainproteaseinvitroandinsilicostudies AT kittikhunwangkanont discoveryofc12dithiocarbamateandrographolideanaloguesasinhibitorsofsarscov2mainproteaseinvitroandinsilicostudies AT patchareearsakhant discoveryofc12dithiocarbamateandrographolideanaloguesasinhibitorsofsarscov2mainproteaseinvitroandinsilicostudies AT rungnaphasaeeng discoveryofc12dithiocarbamateandrographolideanaloguesasinhibitorsofsarscov2mainproteaseinvitroandinsilicostudies AT thanyadarungrotmongkol discoveryofc12dithiocarbamateandrographolideanaloguesasinhibitorsofsarscov2mainproteaseinvitroandinsilicostudies |