Computational analysis of lupenone derivatives as potential inhibitor of human papillomavirus oncoprotein E6 associated cervical cancer
Abstract Cervical cancer remains a major global health challenge, largely driven by persistent infections with high-risk human papillomavirus (HPV). Although preventive vaccines have reduced cervical cancer incidence in some settings, effective therapeutic strategies for established HPV-associated m...
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| Format: | Article |
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Nature Portfolio
2025-05-01
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| Online Access: | https://doi.org/10.1038/s41598-025-96667-3 |
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| author | Saurav Kumar Mishra Mir Md. Shaheen Sharifa Sultana Al-Anood M. Al-Dies Jehad Zuhair Tayyeb Taha Alqahtani Yewulsew Kebede Tiruneh Gabriel Christian de Farias Morais Jonas Ivan Nobre Oliveira Magdi E. A. Zaki |
| author_facet | Saurav Kumar Mishra Mir Md. Shaheen Sharifa Sultana Al-Anood M. Al-Dies Jehad Zuhair Tayyeb Taha Alqahtani Yewulsew Kebede Tiruneh Gabriel Christian de Farias Morais Jonas Ivan Nobre Oliveira Magdi E. A. Zaki |
| author_sort | Saurav Kumar Mishra |
| collection | DOAJ |
| description | Abstract Cervical cancer remains a major global health challenge, largely driven by persistent infections with high-risk human papillomavirus (HPV). Although preventive vaccines have reduced cervical cancer incidence in some settings, effective therapeutic strategies for established HPV-associated malignancies remain limited. High-risk HPV types (particularly 16 and 18) utilize their E6 oncoprotein to promote ubiquitin-mediated degradation of the tumor suppressor p53, thereby facilitating uncontrolled cell proliferation and immune evasion. Targeting E6 has thus emerged as a key strategy to counteract HPV-driven carcinogenesis. In this work, we employed a comprehensive in silico framework—encompassing density functional theory (DFT), ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling, molecular docking (including refinement and validation), and molecular dynamics (MD) simulations—to evaluate a series of chemically modified lupenone derivatives as potential HPV oncoprotein inhibitors. Initially, lupenone was modified with different functional groups, and each derivative was screened for drug-likeness via ADMET analysis to confirm pharmacological viability. Concurrently, pharmacophore mapping highlighted key alignments between ligand functional groups and pharmacophoric sites, while DFT calculations elucidated each compound’s electronic structure, conformational stability, and chemical reactivity. Subsequent docking assessments against E6 oncoprotein and molecular dynamics simulations further confirmed structural robustness in several top-performing compounds, indicating minimal conformational fluctuations over time. These findings demonstrate the potential of lupenone derivatives as promising scaffolds for anti-HPV therapy. However, in vitro and in vivo investigations are necessary to confirm their efficacy, toxicity profiles, and clinical relevance in mitigating HPV-related cervical cancer. |
| format | Article |
| id | doaj-art-75cca614cd58434d90a488ba907726e5 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-75cca614cd58434d90a488ba907726e52025-08-20T03:52:19ZengNature PortfolioScientific Reports2045-23222025-05-0115112210.1038/s41598-025-96667-3Computational analysis of lupenone derivatives as potential inhibitor of human papillomavirus oncoprotein E6 associated cervical cancerSaurav Kumar Mishra0Mir Md. Shaheen1Sharifa Sultana2Al-Anood M. Al-Dies3Jehad Zuhair Tayyeb4Taha Alqahtani5Yewulsew Kebede Tiruneh6Gabriel Christian de Farias Morais7Jonas Ivan Nobre Oliveira 8Magdi E. A. Zaki9Department of Bioinformatics, University of North BengalComputational Biology Research Laboratory, Department of Pharmacy, Daffodil International UniversityComputational Biology Research Laboratory, Department of Pharmacy, Daffodil International UniversityDepartment of Chemistry , Umm Al-Qura University, Al-Qunfudah University CollegeDivision of Clinical Biochemistry, Department of Basic Medical Sciences, College of Medicine, University of JeddahDepartment of Pharmacology, College of Pharmacy, King Khalid UniversityDepartment of Biology, Biomedical Sciences Stream, Bahir Dar UniversityDepartment of Biophysics and Pharmacology, Federal University of Rio Grande do NorteDepartment of Biophysics and Pharmacology, Federal University of Rio Grande do NorteDepartment of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU)Abstract Cervical cancer remains a major global health challenge, largely driven by persistent infections with high-risk human papillomavirus (HPV). Although preventive vaccines have reduced cervical cancer incidence in some settings, effective therapeutic strategies for established HPV-associated malignancies remain limited. High-risk HPV types (particularly 16 and 18) utilize their E6 oncoprotein to promote ubiquitin-mediated degradation of the tumor suppressor p53, thereby facilitating uncontrolled cell proliferation and immune evasion. Targeting E6 has thus emerged as a key strategy to counteract HPV-driven carcinogenesis. In this work, we employed a comprehensive in silico framework—encompassing density functional theory (DFT), ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling, molecular docking (including refinement and validation), and molecular dynamics (MD) simulations—to evaluate a series of chemically modified lupenone derivatives as potential HPV oncoprotein inhibitors. Initially, lupenone was modified with different functional groups, and each derivative was screened for drug-likeness via ADMET analysis to confirm pharmacological viability. Concurrently, pharmacophore mapping highlighted key alignments between ligand functional groups and pharmacophoric sites, while DFT calculations elucidated each compound’s electronic structure, conformational stability, and chemical reactivity. Subsequent docking assessments against E6 oncoprotein and molecular dynamics simulations further confirmed structural robustness in several top-performing compounds, indicating minimal conformational fluctuations over time. These findings demonstrate the potential of lupenone derivatives as promising scaffolds for anti-HPV therapy. However, in vitro and in vivo investigations are necessary to confirm their efficacy, toxicity profiles, and clinical relevance in mitigating HPV-related cervical cancer.https://doi.org/10.1038/s41598-025-96667-3DruglikenessDFTMolecular dockingMolecular dynamic simulationADMETHuman papilloma virus |
| spellingShingle | Saurav Kumar Mishra Mir Md. Shaheen Sharifa Sultana Al-Anood M. Al-Dies Jehad Zuhair Tayyeb Taha Alqahtani Yewulsew Kebede Tiruneh Gabriel Christian de Farias Morais Jonas Ivan Nobre Oliveira Magdi E. A. Zaki Computational analysis of lupenone derivatives as potential inhibitor of human papillomavirus oncoprotein E6 associated cervical cancer Scientific Reports Druglikeness DFT Molecular docking Molecular dynamic simulation ADMET Human papilloma virus |
| title | Computational analysis of lupenone derivatives as potential inhibitor of human papillomavirus oncoprotein E6 associated cervical cancer |
| title_full | Computational analysis of lupenone derivatives as potential inhibitor of human papillomavirus oncoprotein E6 associated cervical cancer |
| title_fullStr | Computational analysis of lupenone derivatives as potential inhibitor of human papillomavirus oncoprotein E6 associated cervical cancer |
| title_full_unstemmed | Computational analysis of lupenone derivatives as potential inhibitor of human papillomavirus oncoprotein E6 associated cervical cancer |
| title_short | Computational analysis of lupenone derivatives as potential inhibitor of human papillomavirus oncoprotein E6 associated cervical cancer |
| title_sort | computational analysis of lupenone derivatives as potential inhibitor of human papillomavirus oncoprotein e6 associated cervical cancer |
| topic | Druglikeness DFT Molecular docking Molecular dynamic simulation ADMET Human papilloma virus |
| url | https://doi.org/10.1038/s41598-025-96667-3 |
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