Discovery of natural scaffolds as HER2 inhibitors for breast cancer: virtual screening, molecular dynamics, and biological characterization with selectivity profiling
Abstract Nature offers potential therapeutic candidates for breast cancer (BC), and targeting HER2 signaling presents a promising approach, leveraging the successful history of anticancer drug discovery. Using a structure-based virtual screening workflow, a comprehensive library of natural products...
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Nature Portfolio
2025-07-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-11177-6 |
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| author | Asmaa Hossam Ingy I. Abdallah Nadia A. El-Sebakhy Radwan Alnajjar Mohamed M. Mohyeldin |
| author_facet | Asmaa Hossam Ingy I. Abdallah Nadia A. El-Sebakhy Radwan Alnajjar Mohamed M. Mohyeldin |
| author_sort | Asmaa Hossam |
| collection | DOAJ |
| description | Abstract Nature offers potential therapeutic candidates for breast cancer (BC), and targeting HER2 signaling presents a promising approach, leveraging the successful history of anticancer drug discovery. Using a structure-based virtual screening workflow, a comprehensive library of natural products (NPs) was screened for potential HER2 binding. Five of these NPs were selected for in-depth biological validation against BC. Biochemically, oroxin B, liquiritin, ligustroflavone, and mulberroside A suppressed HER2 catalysis with nanomolar potency. Binding mode studies of NPs revealed their binding patterns, providing valuable SAR insights for effective HER2 inhibition. Further cellular assays revealed that the top NPs have preferential anti-proliferative effects towards HER2 over-expressing BC cells, with notable selectivity indices. Liquiritin exhibited promising anti-migratory activity in two cellular motility models, while other tested hits primarily inhibited cancer cell growth with minimal effects on metastasis. Liquiritin and oroxin B stood out as validated hits, revealing the most promising profiles. ADME predictions and MD simulations positioned liquiritin as a more promising HER2 inhibitor than oroxin B, despite oroxin B’s higher ranking in rigid docking studies. On the molecular level, liquiritin significantly inhibited HER2 phosphorylation and expression in BC cells. Liquiritin demonstrated notable selectivity for HER family proteins when tested against various kinases, highlighting its potential as a pan-HER inhibitor hit for future development. Further in vivo assessment is necessary to support the hit-to-lead promotion of liquiritin. |
| format | Article |
| id | doaj-art-adc32aaad4dd467eae7c321e4c7fea6d |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-adc32aaad4dd467eae7c321e4c7fea6d2025-08-20T04:02:46ZengNature PortfolioScientific Reports2045-23222025-07-0115112210.1038/s41598-025-11177-6Discovery of natural scaffolds as HER2 inhibitors for breast cancer: virtual screening, molecular dynamics, and biological characterization with selectivity profilingAsmaa Hossam0Ingy I. Abdallah1Nadia A. El-Sebakhy2Radwan Alnajjar3Mohamed M. Mohyeldin4Department of Pharmacognosy, Faculty of Pharmacy, Alexandria UniversityDepartment of Pharmacognosy, Faculty of Pharmacy, Alexandria UniversityDepartment of Pharmacognosy, Faculty of Pharmacy, Alexandria UniversityDepartment of Chemistry, Faculty of Science, University of BenghaziDepartment of Pharmacognosy, Faculty of Pharmacy, Alexandria UniversityAbstract Nature offers potential therapeutic candidates for breast cancer (BC), and targeting HER2 signaling presents a promising approach, leveraging the successful history of anticancer drug discovery. Using a structure-based virtual screening workflow, a comprehensive library of natural products (NPs) was screened for potential HER2 binding. Five of these NPs were selected for in-depth biological validation against BC. Biochemically, oroxin B, liquiritin, ligustroflavone, and mulberroside A suppressed HER2 catalysis with nanomolar potency. Binding mode studies of NPs revealed their binding patterns, providing valuable SAR insights for effective HER2 inhibition. Further cellular assays revealed that the top NPs have preferential anti-proliferative effects towards HER2 over-expressing BC cells, with notable selectivity indices. Liquiritin exhibited promising anti-migratory activity in two cellular motility models, while other tested hits primarily inhibited cancer cell growth with minimal effects on metastasis. Liquiritin and oroxin B stood out as validated hits, revealing the most promising profiles. ADME predictions and MD simulations positioned liquiritin as a more promising HER2 inhibitor than oroxin B, despite oroxin B’s higher ranking in rigid docking studies. On the molecular level, liquiritin significantly inhibited HER2 phosphorylation and expression in BC cells. Liquiritin demonstrated notable selectivity for HER family proteins when tested against various kinases, highlighting its potential as a pan-HER inhibitor hit for future development. Further in vivo assessment is necessary to support the hit-to-lead promotion of liquiritin.https://doi.org/10.1038/s41598-025-11177-6Breast cancerVirtual screeningHER2Western blotMolecular dynamicsLiquiritin |
| spellingShingle | Asmaa Hossam Ingy I. Abdallah Nadia A. El-Sebakhy Radwan Alnajjar Mohamed M. Mohyeldin Discovery of natural scaffolds as HER2 inhibitors for breast cancer: virtual screening, molecular dynamics, and biological characterization with selectivity profiling Scientific Reports Breast cancer Virtual screening HER2 Western blot Molecular dynamics Liquiritin |
| title | Discovery of natural scaffolds as HER2 inhibitors for breast cancer: virtual screening, molecular dynamics, and biological characterization with selectivity profiling |
| title_full | Discovery of natural scaffolds as HER2 inhibitors for breast cancer: virtual screening, molecular dynamics, and biological characterization with selectivity profiling |
| title_fullStr | Discovery of natural scaffolds as HER2 inhibitors for breast cancer: virtual screening, molecular dynamics, and biological characterization with selectivity profiling |
| title_full_unstemmed | Discovery of natural scaffolds as HER2 inhibitors for breast cancer: virtual screening, molecular dynamics, and biological characterization with selectivity profiling |
| title_short | Discovery of natural scaffolds as HER2 inhibitors for breast cancer: virtual screening, molecular dynamics, and biological characterization with selectivity profiling |
| title_sort | discovery of natural scaffolds as her2 inhibitors for breast cancer virtual screening molecular dynamics and biological characterization with selectivity profiling |
| topic | Breast cancer Virtual screening HER2 Western blot Molecular dynamics Liquiritin |
| url | https://doi.org/10.1038/s41598-025-11177-6 |
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