Leveraging computational approaches in identifying novel HER-2 + breast cancer potential therapeutics: integrating virtual screening and molecular dynamics simulation
Abstract Background Breast cancer, particularly the human epidermal growth factor receptor 2 positive subtype, presents a significant global health challenge due to its high prevalence and mortality rates. This study delves into the molecular intricacies of HER-2 positive breast cancer, with an emph...
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| Format: | Article |
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SpringerOpen
2025-01-01
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| Series: | Future Journal of Pharmaceutical Sciences |
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| Online Access: | https://doi.org/10.1186/s43094-024-00748-5 |
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| author | Olawale Quadri Bolaji Temitope Isaac Adelusi Taiwo Ooreoluwa Ojo Ibrahim Damilare Boyenle Abdul-Quddus Kehinde Oyedele Taiwo Temitope Ogunjobi Adegboye Oyewole Oyaronbi Sukurat Oluwatoyin Ayoola Abdeen Tunde Ogunlana |
| author_facet | Olawale Quadri Bolaji Temitope Isaac Adelusi Taiwo Ooreoluwa Ojo Ibrahim Damilare Boyenle Abdul-Quddus Kehinde Oyedele Taiwo Temitope Ogunjobi Adegboye Oyewole Oyaronbi Sukurat Oluwatoyin Ayoola Abdeen Tunde Ogunlana |
| author_sort | Olawale Quadri Bolaji |
| collection | DOAJ |
| description | Abstract Background Breast cancer, particularly the human epidermal growth factor receptor 2 positive subtype, presents a significant global health challenge due to its high prevalence and mortality rates. This study delves into the molecular intricacies of HER-2 positive breast cancer, with an emphasis on the role of the HER-2 oncoprotein and its associated signaling pathways in cell growth, differentiation, and survival. In our pursuit of overcoming the limitations of one of the leading therapeutic options, Lapatinib, such as its inhibition of hERG, we embarked on a comprehensive research journey. Result This study involved dual-stage molecular docking, initially with a library of PubChem-curated compounds, revealing Compound 90196902 as the best of the set. This was followed by the docking of DataWarrior-generated structural analogs of Compound 90196902, using various docking protocols such as standard precision, extra precision, and induced fit docking. Through this rigorous screening protocol, three promising drug candidates (Compound_56, Compound_81, and Compound_339) were identified, showing excellent interaction with the target. Additionally, binding free energy calculations, ADME and toxicity profiling, and molecular dynamics simulations presented these compounds as lead-like. Conclusion Compound_56 showed the most promising pharmacodynamic and pharmacokinetic properties, coupled with substantial structural stability. While immensely promising, further optimization and pre-clinical investigation are imperative to validate this compound as a viable alternative to existing therapies for HER-2 positive breast cancer. Graphical abstract |
| format | Article |
| id | doaj-art-394a0aecfc7c4af698369be8f3110407 |
| institution | Kabale University |
| issn | 2314-7253 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | Future Journal of Pharmaceutical Sciences |
| spelling | doaj-art-394a0aecfc7c4af698369be8f31104072025-01-12T12:11:10ZengSpringerOpenFuture Journal of Pharmaceutical Sciences2314-72532025-01-0111111710.1186/s43094-024-00748-5Leveraging computational approaches in identifying novel HER-2 + breast cancer potential therapeutics: integrating virtual screening and molecular dynamics simulationOlawale Quadri Bolaji0Temitope Isaac Adelusi1Taiwo Ooreoluwa Ojo2Ibrahim Damilare Boyenle3Abdul-Quddus Kehinde Oyedele4Taiwo Temitope Ogunjobi5Adegboye Oyewole Oyaronbi6Sukurat Oluwatoyin Ayoola7Abdeen Tunde Ogunlana8National Institute For Pharmaceutical Research and DevelopmentDepartment of Surgery, School of Medicine, University of Connecticut HealthChemiron Care Ltd, Agbara Industrial EstateDepartment of Chemistry and Biochemistry, University of MarylandDepartment of Chemistry, University of New HavenDepartment of Biochemistry, Ladoke Akintola University of TechnologyDepartment of Biochemistry, Ladoke Akintola University of TechnologyDepartment of Public Health, College of Medicine, University of IbadanInstitute for Advanced Medical Research and Training, College of Medicine, University of IbadanAbstract Background Breast cancer, particularly the human epidermal growth factor receptor 2 positive subtype, presents a significant global health challenge due to its high prevalence and mortality rates. This study delves into the molecular intricacies of HER-2 positive breast cancer, with an emphasis on the role of the HER-2 oncoprotein and its associated signaling pathways in cell growth, differentiation, and survival. In our pursuit of overcoming the limitations of one of the leading therapeutic options, Lapatinib, such as its inhibition of hERG, we embarked on a comprehensive research journey. Result This study involved dual-stage molecular docking, initially with a library of PubChem-curated compounds, revealing Compound 90196902 as the best of the set. This was followed by the docking of DataWarrior-generated structural analogs of Compound 90196902, using various docking protocols such as standard precision, extra precision, and induced fit docking. Through this rigorous screening protocol, three promising drug candidates (Compound_56, Compound_81, and Compound_339) were identified, showing excellent interaction with the target. Additionally, binding free energy calculations, ADME and toxicity profiling, and molecular dynamics simulations presented these compounds as lead-like. Conclusion Compound_56 showed the most promising pharmacodynamic and pharmacokinetic properties, coupled with substantial structural stability. While immensely promising, further optimization and pre-clinical investigation are imperative to validate this compound as a viable alternative to existing therapies for HER-2 positive breast cancer. Graphical abstracthttps://doi.org/10.1186/s43094-024-00748-5Breast cancerHER-2Molecular dockingInduced fit dockingMolecular dynamics simulationADMET profiling |
| spellingShingle | Olawale Quadri Bolaji Temitope Isaac Adelusi Taiwo Ooreoluwa Ojo Ibrahim Damilare Boyenle Abdul-Quddus Kehinde Oyedele Taiwo Temitope Ogunjobi Adegboye Oyewole Oyaronbi Sukurat Oluwatoyin Ayoola Abdeen Tunde Ogunlana Leveraging computational approaches in identifying novel HER-2 + breast cancer potential therapeutics: integrating virtual screening and molecular dynamics simulation Future Journal of Pharmaceutical Sciences Breast cancer HER-2 Molecular docking Induced fit docking Molecular dynamics simulation ADMET profiling |
| title | Leveraging computational approaches in identifying novel HER-2 + breast cancer potential therapeutics: integrating virtual screening and molecular dynamics simulation |
| title_full | Leveraging computational approaches in identifying novel HER-2 + breast cancer potential therapeutics: integrating virtual screening and molecular dynamics simulation |
| title_fullStr | Leveraging computational approaches in identifying novel HER-2 + breast cancer potential therapeutics: integrating virtual screening and molecular dynamics simulation |
| title_full_unstemmed | Leveraging computational approaches in identifying novel HER-2 + breast cancer potential therapeutics: integrating virtual screening and molecular dynamics simulation |
| title_short | Leveraging computational approaches in identifying novel HER-2 + breast cancer potential therapeutics: integrating virtual screening and molecular dynamics simulation |
| title_sort | leveraging computational approaches in identifying novel her 2 breast cancer potential therapeutics integrating virtual screening and molecular dynamics simulation |
| topic | Breast cancer HER-2 Molecular docking Induced fit docking Molecular dynamics simulation ADMET profiling |
| url | https://doi.org/10.1186/s43094-024-00748-5 |
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