Computer-guided identification of novel inhibitors of apoptosis-signaling kinase 1 from Spondia mombim bioactive compounds against colorectal cancer
Abstract Background Apoptosis-signaling kinase 1 is a MAPKKK (mitogen-activated protein kinase) overexpressed in various types of human cancer including colorectal cancer. It mediates inflammation and apoptosis and promotes cell proliferation through the transcription of cyclin D1. 5-Fluorouracil re...
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2025-01-01
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| Series: | Egyptian Journal of Medical Human Genetics |
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| Online Access: | https://doi.org/10.1186/s43042-024-00625-z |
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| author | Olusola Olalekan Elekofehinti Hannah Oluwaseun Popoola Adedotun Olayemi Oluwatuyi Opeyemi Iwaloye Moses Orimoloye Akinjiyan Oluwamodupe Cecilia Frank Abimbola Ogundolie Olalekan Isaac Olatunde Oussama Abchir Samir Chtita Joao Batista Texeira Rocha |
| author_facet | Olusola Olalekan Elekofehinti Hannah Oluwaseun Popoola Adedotun Olayemi Oluwatuyi Opeyemi Iwaloye Moses Orimoloye Akinjiyan Oluwamodupe Cecilia Frank Abimbola Ogundolie Olalekan Isaac Olatunde Oussama Abchir Samir Chtita Joao Batista Texeira Rocha |
| author_sort | Olusola Olalekan Elekofehinti |
| collection | DOAJ |
| description | Abstract Background Apoptosis-signaling kinase 1 is a MAPKKK (mitogen-activated protein kinase) overexpressed in various types of human cancer including colorectal cancer. It mediates inflammation and apoptosis and promotes cell proliferation through the transcription of cyclin D1. 5-Fluorouracil remains one of the primary recommended drugs to manage colorectal cancer. However, this drug often causes various adverse effects, notably diarrhea, vomiting, nausea, and leukopenia. Therefore, a novel treatment is required to eradicate these problems. The clinical implication of apoptosis-signaling kinase 1 in the pathogenicity of colorectal cancer makes it an important drug target in the treatment of colorectal cancer. The use of natural compounds in human cancer treatment continues to gain significant attention in the scientific community due to their therapeutic efficacy. Method In this study, computational models such as flexible docking, induced fit docking, and binding free energy calculation were employed to identify small molecule inhibitors from known bioactive compounds of Spondias mombin in reference to 5-fluorouracil (Colorectal cancer standard drug) targeting apoptosis-signaling kinase 1. Results Molecular docking studies identified 10 promising candidates which include uvaretin, rutin, isoquercitrin, ellagic acid, quercetin, linalool, acetyl eugenol, tangeretin (-)-catechin, and d-sorbitol based on their favorable binding affinity, with uvaretin having the best score (− 11.328 kcal/mol). The results were further validated with more dependable analysis such as induced fit docking and binding free energy calculation. These compounds showed modest indices for ADMET parameters. Molecular dynamic simulation validated ellagic acid and (-)-catechin with greater binding stability as leading compounds. Conclusion These compounds showed improved flexible docking results and formed considerable stable interaction with the protein than 5-fluorouracil. They are non-carcinogenic. The oral bioavailability and toxicities of these compounds are promising as compounds obeyed the Lipinski rule of five. The constructed quantitative structure–activity relationship model with a trustworthy R 2 coefficient value supports the inhibition prowess of these compounds. The findings from this research confer that these compounds could be considered potent apoptosis-signaling kinase 1 inhibitors, and these could be confirmed experimentally as lead compounds of apoptosis-signaling kinase 1 inhibitors in colorectal cancer. |
| format | Article |
| id | doaj-art-5a17d3059bfa4e5383c7e8377b8ba201 |
| institution | Kabale University |
| issn | 2090-2441 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | SpringerOpen |
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| series | Egyptian Journal of Medical Human Genetics |
| spelling | doaj-art-5a17d3059bfa4e5383c7e8377b8ba2012025-01-19T12:25:56ZengSpringerOpenEgyptian Journal of Medical Human Genetics2090-24412025-01-0126112210.1186/s43042-024-00625-zComputer-guided identification of novel inhibitors of apoptosis-signaling kinase 1 from Spondia mombim bioactive compounds against colorectal cancerOlusola Olalekan Elekofehinti0Hannah Oluwaseun Popoola1Adedotun Olayemi Oluwatuyi2Opeyemi Iwaloye3Moses Orimoloye Akinjiyan4Oluwamodupe Cecilia5Frank Abimbola Ogundolie6Olalekan Isaac Olatunde7Oussama Abchir8Samir Chtita9Joao Batista Texeira Rocha10Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology AkureBioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology AkureBioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology AkureBioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology AkureBioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology AkurePhytomedicine, Molecular Biology and Bioinformatics Laboratory, Department of Chemical Science (Biochemistry Program), Olusegun Agagu University of Science and TechnologyDepartment of Biotechnology, Baze UniversityImported Food Unit, National Agency for Food and Drug Administration and ControlLaboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M’Sik, Hassan II University of CasablancaLaboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M’Sik, Hassan II University of CasablancaBiochemical Toxicology Unit, Department of Biochemistry and Molecular Biology, CCNE, Universidade Federal de Santa MariaAbstract Background Apoptosis-signaling kinase 1 is a MAPKKK (mitogen-activated protein kinase) overexpressed in various types of human cancer including colorectal cancer. It mediates inflammation and apoptosis and promotes cell proliferation through the transcription of cyclin D1. 5-Fluorouracil remains one of the primary recommended drugs to manage colorectal cancer. However, this drug often causes various adverse effects, notably diarrhea, vomiting, nausea, and leukopenia. Therefore, a novel treatment is required to eradicate these problems. The clinical implication of apoptosis-signaling kinase 1 in the pathogenicity of colorectal cancer makes it an important drug target in the treatment of colorectal cancer. The use of natural compounds in human cancer treatment continues to gain significant attention in the scientific community due to their therapeutic efficacy. Method In this study, computational models such as flexible docking, induced fit docking, and binding free energy calculation were employed to identify small molecule inhibitors from known bioactive compounds of Spondias mombin in reference to 5-fluorouracil (Colorectal cancer standard drug) targeting apoptosis-signaling kinase 1. Results Molecular docking studies identified 10 promising candidates which include uvaretin, rutin, isoquercitrin, ellagic acid, quercetin, linalool, acetyl eugenol, tangeretin (-)-catechin, and d-sorbitol based on their favorable binding affinity, with uvaretin having the best score (− 11.328 kcal/mol). The results were further validated with more dependable analysis such as induced fit docking and binding free energy calculation. These compounds showed modest indices for ADMET parameters. Molecular dynamic simulation validated ellagic acid and (-)-catechin with greater binding stability as leading compounds. Conclusion These compounds showed improved flexible docking results and formed considerable stable interaction with the protein than 5-fluorouracil. They are non-carcinogenic. The oral bioavailability and toxicities of these compounds are promising as compounds obeyed the Lipinski rule of five. The constructed quantitative structure–activity relationship model with a trustworthy R 2 coefficient value supports the inhibition prowess of these compounds. The findings from this research confer that these compounds could be considered potent apoptosis-signaling kinase 1 inhibitors, and these could be confirmed experimentally as lead compounds of apoptosis-signaling kinase 1 inhibitors in colorectal cancer.https://doi.org/10.1186/s43042-024-00625-zColorectal cancerASK 1Molecular dockingNovel inhibitorsSpondias mombin5-Fluorouracil |
| spellingShingle | Olusola Olalekan Elekofehinti Hannah Oluwaseun Popoola Adedotun Olayemi Oluwatuyi Opeyemi Iwaloye Moses Orimoloye Akinjiyan Oluwamodupe Cecilia Frank Abimbola Ogundolie Olalekan Isaac Olatunde Oussama Abchir Samir Chtita Joao Batista Texeira Rocha Computer-guided identification of novel inhibitors of apoptosis-signaling kinase 1 from Spondia mombim bioactive compounds against colorectal cancer Egyptian Journal of Medical Human Genetics Colorectal cancer ASK 1 Molecular docking Novel inhibitors Spondias mombin 5-Fluorouracil |
| title | Computer-guided identification of novel inhibitors of apoptosis-signaling kinase 1 from Spondia mombim bioactive compounds against colorectal cancer |
| title_full | Computer-guided identification of novel inhibitors of apoptosis-signaling kinase 1 from Spondia mombim bioactive compounds against colorectal cancer |
| title_fullStr | Computer-guided identification of novel inhibitors of apoptosis-signaling kinase 1 from Spondia mombim bioactive compounds against colorectal cancer |
| title_full_unstemmed | Computer-guided identification of novel inhibitors of apoptosis-signaling kinase 1 from Spondia mombim bioactive compounds against colorectal cancer |
| title_short | Computer-guided identification of novel inhibitors of apoptosis-signaling kinase 1 from Spondia mombim bioactive compounds against colorectal cancer |
| title_sort | computer guided identification of novel inhibitors of apoptosis signaling kinase 1 from spondia mombim bioactive compounds against colorectal cancer |
| topic | Colorectal cancer ASK 1 Molecular docking Novel inhibitors Spondias mombin 5-Fluorouracil |
| url | https://doi.org/10.1186/s43042-024-00625-z |
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