A multi-targeted computational drug discovery approach for repurposing tetracyclines against monkeypox virus
Abstract Monkeypox viral infection is an emerging threat and a major concern for the human population. The lack of drug molecules to treat this disease may worsen the problem. Identifying potential drug targets can significantly improve the process of developing potent drug molecules for treating mo...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-09-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-41820-z |
| _version_ | 1797452632461148160 |
|---|---|
| author | Thamir A. Alandijany Mai M. El-Daly Ahmed M. Tolah Leena H. Bajrai Aiah M. Khateb Geethu S. Kumar Amit Dubey Vivek Dhar Dwivedi Esam I. Azhar |
| author_facet | Thamir A. Alandijany Mai M. El-Daly Ahmed M. Tolah Leena H. Bajrai Aiah M. Khateb Geethu S. Kumar Amit Dubey Vivek Dhar Dwivedi Esam I. Azhar |
| author_sort | Thamir A. Alandijany |
| collection | DOAJ |
| description | Abstract Monkeypox viral infection is an emerging threat and a major concern for the human population. The lack of drug molecules to treat this disease may worsen the problem. Identifying potential drug targets can significantly improve the process of developing potent drug molecules for treating monkeypox. The proteins responsible for viral replication are attractive drug targets. Identifying potential inhibitors from known drug molecules that target these proteins can be key to finding a cure for monkeypox. In this work, two viral proteins, DNA-dependent RNA polymerase (DdRp) and viral core cysteine proteinase, were considered as potential drug targets. Sixteen antibiotic drugs from the tetracycline class were screened against both viral proteins through high-throughput virtual screening. These tetracycline class of antibiotic drugs have the ability to inhibit bacterial protein synthesis, which makes these antibiotics drugs a prominent candidate for drug repurposing. Based on the screening result obtained against DdRp, top two compounds, namely Tigecycline and Eravacycline with docking scores of − 8.88 and − 7.87 kcal/mol, respectively, were selected for further analysis. Omadacycline and minocycline, with docking scores of − 10.60 and − 7.51 kcal/mol, are the top two compounds obtained after screening proteinase with the drug library. These compounds, along with reference compounds GTP for DdRp and tecovirimat for proteinase, were used to form protein–ligand complexes, followed by their evaluation through a 300 ns molecular dynamic simulation. The MM/GBSA binding free energy calculation and principal components analysis of these selected complexes were also conducted for understanding the dynamic stability and binding affinity of these compounds with respective target proteins. Overall, this study demonstrates the repurposing of tetracycline-derived drugs as a therapeutic solution for monkeypox viral infection. |
| first_indexed | 2024-03-09T15:11:27Z |
| format | Article |
| id | doaj.art-1bbe39f1219e42f9bf4b62f13418f022 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-09T15:11:27Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-1bbe39f1219e42f9bf4b62f13418f0222023-11-26T13:19:22ZengNature PortfolioScientific Reports2045-23222023-09-0113112210.1038/s41598-023-41820-zA multi-targeted computational drug discovery approach for repurposing tetracyclines against monkeypox virusThamir A. Alandijany0Mai M. El-Daly1Ahmed M. Tolah2Leena H. Bajrai3Aiah M. Khateb4Geethu S. Kumar5Amit Dubey6Vivek Dhar Dwivedi7Esam I. Azhar8Special Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz UniversitySpecial Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz UniversitySpecial Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz UniversitySpecial Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz UniversitySpecial Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz UniversityDepartment of Life Science, School of Basic Science and Research, Sharda UniversityComputational Chemistry and Drug Discovery Division, Quanta CalculusBioinformatics Research Division, Quanta CalculusSpecial Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz UniversityAbstract Monkeypox viral infection is an emerging threat and a major concern for the human population. The lack of drug molecules to treat this disease may worsen the problem. Identifying potential drug targets can significantly improve the process of developing potent drug molecules for treating monkeypox. The proteins responsible for viral replication are attractive drug targets. Identifying potential inhibitors from known drug molecules that target these proteins can be key to finding a cure for monkeypox. In this work, two viral proteins, DNA-dependent RNA polymerase (DdRp) and viral core cysteine proteinase, were considered as potential drug targets. Sixteen antibiotic drugs from the tetracycline class were screened against both viral proteins through high-throughput virtual screening. These tetracycline class of antibiotic drugs have the ability to inhibit bacterial protein synthesis, which makes these antibiotics drugs a prominent candidate for drug repurposing. Based on the screening result obtained against DdRp, top two compounds, namely Tigecycline and Eravacycline with docking scores of − 8.88 and − 7.87 kcal/mol, respectively, were selected for further analysis. Omadacycline and minocycline, with docking scores of − 10.60 and − 7.51 kcal/mol, are the top two compounds obtained after screening proteinase with the drug library. These compounds, along with reference compounds GTP for DdRp and tecovirimat for proteinase, were used to form protein–ligand complexes, followed by their evaluation through a 300 ns molecular dynamic simulation. The MM/GBSA binding free energy calculation and principal components analysis of these selected complexes were also conducted for understanding the dynamic stability and binding affinity of these compounds with respective target proteins. Overall, this study demonstrates the repurposing of tetracycline-derived drugs as a therapeutic solution for monkeypox viral infection.https://doi.org/10.1038/s41598-023-41820-z |
| spellingShingle | Thamir A. Alandijany Mai M. El-Daly Ahmed M. Tolah Leena H. Bajrai Aiah M. Khateb Geethu S. Kumar Amit Dubey Vivek Dhar Dwivedi Esam I. Azhar A multi-targeted computational drug discovery approach for repurposing tetracyclines against monkeypox virus Scientific Reports |
| title | A multi-targeted computational drug discovery approach for repurposing tetracyclines against monkeypox virus |
| title_full | A multi-targeted computational drug discovery approach for repurposing tetracyclines against monkeypox virus |
| title_fullStr | A multi-targeted computational drug discovery approach for repurposing tetracyclines against monkeypox virus |
| title_full_unstemmed | A multi-targeted computational drug discovery approach for repurposing tetracyclines against monkeypox virus |
| title_short | A multi-targeted computational drug discovery approach for repurposing tetracyclines against monkeypox virus |
| title_sort | multi targeted computational drug discovery approach for repurposing tetracyclines against monkeypox virus |
| url | https://doi.org/10.1038/s41598-023-41820-z |
| work_keys_str_mv | AT thamiraalandijany amultitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT maimeldaly amultitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT ahmedmtolah amultitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT leenahbajrai amultitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT aiahmkhateb amultitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT geethuskumar amultitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT amitdubey amultitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT vivekdhardwivedi amultitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT esamiazhar amultitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT thamiraalandijany multitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT maimeldaly multitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT ahmedmtolah multitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT leenahbajrai multitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT aiahmkhateb multitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT geethuskumar multitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT amitdubey multitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT vivekdhardwivedi multitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus AT esamiazhar multitargetedcomputationaldrugdiscoveryapproachforrepurposingtetracyclinesagainstmonkeypoxvirus |