Molecular modelling studies and in vitro enzymatic assays identified A 4-(nitrobenzyl)guanidine derivative as inhibitor of SARS-CoV-2 Mpro
Abstract Scientists and researchers have been searching for drugs targeting the main protease (Mpro) of SARS-CoV-2, which is crucial for virus replication. This study employed a virtual screening based on molecular docking to identify benzoylguanidines from an in-house chemical library that can inhi...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-04-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-59292-0 |
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| author | Kaio Maciel de Santiago-Silva Priscila Goes Camargo Larissa Esteves Carvalho Constant Stephany da Silva Costa Giovanna Barbosa Frensel Diego Allonso Gerson Nakazato Camilo Henrique da Silva Lima Marcelle de Lima Ferreira Bispo |
| author_facet | Kaio Maciel de Santiago-Silva Priscila Goes Camargo Larissa Esteves Carvalho Constant Stephany da Silva Costa Giovanna Barbosa Frensel Diego Allonso Gerson Nakazato Camilo Henrique da Silva Lima Marcelle de Lima Ferreira Bispo |
| author_sort | Kaio Maciel de Santiago-Silva |
| collection | DOAJ |
| description | Abstract Scientists and researchers have been searching for drugs targeting the main protease (Mpro) of SARS-CoV-2, which is crucial for virus replication. This study employed a virtual screening based on molecular docking to identify benzoylguanidines from an in-house chemical library that can inhibit Mpro on the active site and three allosteric sites. Molecular docking was performed on the LaSMMed Chemical Library using 88 benzoylguanidine compounds. Based on their RMSD values and conserved pose, three potential inhibitors (BZG1, BZG2, and BZG3) were selected. These results indicate that BZG1 and BZG3 may bind to the active site, while BZG2 may bind to allosteric sites. Molecular dynamics data suggest that BZG2 selectively targets allosteric site 3. In vitro tests were performed to measure the proteolytic activity of rMpro. The tests showed that BZG2 has uncompetitive inhibitory activity, with an IC50 value of 77 µM. These findings suggest that benzoylguanidines possess potential as Mpro inhibitors and pave the way towards combating SARS-Cov-2 effectively. |
| first_indexed | 2024-04-24T07:16:44Z |
| format | Article |
| id | doaj.art-ce15e21da1944d63a519ca082f6675a0 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-24T07:16:44Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-ce15e21da1944d63a519ca082f6675a02024-04-21T11:18:31ZengNature PortfolioScientific Reports2045-23222024-04-0114111510.1038/s41598-024-59292-0Molecular modelling studies and in vitro enzymatic assays identified A 4-(nitrobenzyl)guanidine derivative as inhibitor of SARS-CoV-2 MproKaio Maciel de Santiago-Silva0Priscila Goes Camargo1Larissa Esteves Carvalho Constant2Stephany da Silva Costa3Giovanna Barbosa Frensel4Diego Allonso5Gerson Nakazato6Camilo Henrique da Silva Lima7Marcelle de Lima Ferreira Bispo8Laboratório de Síntese de Moléculas Medicinais (LaSMMed), Departamento de Química, Centro de Ciências Exatas, Universidade Estadual de LondrinaLaboratório de Síntese de Moléculas Medicinais (LaSMMed), Departamento de Química, Centro de Ciências Exatas, Universidade Estadual de LondrinaDepartamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de JaneiroDepartamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de JaneiroDepartamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de JaneiroDepartamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de JaneiroDepartamento de Microbiologia, Centro de Ciências Biológicas, Universidade Estadual de LondrinaDepartamento de Química Orgânica, Instituto de Química, Universidade Federal Do Rio de JaneiroLaboratório de Síntese de Moléculas Medicinais (LaSMMed), Departamento de Química, Centro de Ciências Exatas, Universidade Estadual de LondrinaAbstract Scientists and researchers have been searching for drugs targeting the main protease (Mpro) of SARS-CoV-2, which is crucial for virus replication. This study employed a virtual screening based on molecular docking to identify benzoylguanidines from an in-house chemical library that can inhibit Mpro on the active site and three allosteric sites. Molecular docking was performed on the LaSMMed Chemical Library using 88 benzoylguanidine compounds. Based on their RMSD values and conserved pose, three potential inhibitors (BZG1, BZG2, and BZG3) were selected. These results indicate that BZG1 and BZG3 may bind to the active site, while BZG2 may bind to allosteric sites. Molecular dynamics data suggest that BZG2 selectively targets allosteric site 3. In vitro tests were performed to measure the proteolytic activity of rMpro. The tests showed that BZG2 has uncompetitive inhibitory activity, with an IC50 value of 77 µM. These findings suggest that benzoylguanidines possess potential as Mpro inhibitors and pave the way towards combating SARS-Cov-2 effectively.https://doi.org/10.1038/s41598-024-59292-03CL proteaseMolecular dockingMolecular dynamicsInhibitorsCoronavirusCOVID-19 |
| spellingShingle | Kaio Maciel de Santiago-Silva Priscila Goes Camargo Larissa Esteves Carvalho Constant Stephany da Silva Costa Giovanna Barbosa Frensel Diego Allonso Gerson Nakazato Camilo Henrique da Silva Lima Marcelle de Lima Ferreira Bispo Molecular modelling studies and in vitro enzymatic assays identified A 4-(nitrobenzyl)guanidine derivative as inhibitor of SARS-CoV-2 Mpro Scientific Reports 3CL protease Molecular docking Molecular dynamics Inhibitors Coronavirus COVID-19 |
| title | Molecular modelling studies and in vitro enzymatic assays identified A 4-(nitrobenzyl)guanidine derivative as inhibitor of SARS-CoV-2 Mpro |
| title_full | Molecular modelling studies and in vitro enzymatic assays identified A 4-(nitrobenzyl)guanidine derivative as inhibitor of SARS-CoV-2 Mpro |
| title_fullStr | Molecular modelling studies and in vitro enzymatic assays identified A 4-(nitrobenzyl)guanidine derivative as inhibitor of SARS-CoV-2 Mpro |
| title_full_unstemmed | Molecular modelling studies and in vitro enzymatic assays identified A 4-(nitrobenzyl)guanidine derivative as inhibitor of SARS-CoV-2 Mpro |
| title_short | Molecular modelling studies and in vitro enzymatic assays identified A 4-(nitrobenzyl)guanidine derivative as inhibitor of SARS-CoV-2 Mpro |
| title_sort | molecular modelling studies and in vitro enzymatic assays identified a 4 nitrobenzyl guanidine derivative as inhibitor of sars cov 2 mpro |
| topic | 3CL protease Molecular docking Molecular dynamics Inhibitors Coronavirus COVID-19 |
| url | https://doi.org/10.1038/s41598-024-59292-0 |
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