The effect of protein mutations on drug binding suggests ensuing personalised drug selection
<p dir="ltr">The advent of personalised medicine promises a deeper understanding of mechanisms and therefore therapies. However, the connection between genomic sequences and clinical treatments is often unclear. We studied 50 breast cancer patients belonging to a population-cohort in...
محفوظ في:
| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , , , , |
| منشور في: |
2021
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| الموضوعات: | |
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| _version_ | 1864513522182914048 |
|---|---|
| author | Shunzhou Wan (1361247) |
| author2 | Deepak Kumar (63095) Valentin Ilyin (2368732) Ussama Al Homsi (14442150) Gulab Sher (12984698) Alexander Knuth (11104) Peter V. Coveney (418676) |
| author2_role | author author author author author author |
| author_facet | Shunzhou Wan (1361247) Deepak Kumar (63095) Valentin Ilyin (2368732) Ussama Al Homsi (14442150) Gulab Sher (12984698) Alexander Knuth (11104) Peter V. Coveney (418676) |
| author_role | author |
| dc.creator.none.fl_str_mv | Shunzhou Wan (1361247) Deepak Kumar (63095) Valentin Ilyin (2368732) Ussama Al Homsi (14442150) Gulab Sher (12984698) Alexander Knuth (11104) Peter V. Coveney (418676) |
| dc.date.none.fl_str_mv | 2021-06-29T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41598-021-92785-w |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/The_effect_of_protein_mutations_on_drug_binding_suggests_ensuing_personalised_drug_selection/31444714 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics Biomedical and clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences Breast cancer Genetics research Molecular dynamics Molecular medicine Nuclear receptors Predictive markers |
| dc.title.none.fl_str_mv | The effect of protein mutations on drug binding suggests ensuing personalised drug selection |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">The advent of personalised medicine promises a deeper understanding of mechanisms and therefore therapies. However, the connection between genomic sequences and clinical treatments is often unclear. We studied 50 breast cancer patients belonging to a population-cohort in the state of Qatar. From Sanger sequencing, we identified several new deleterious mutations in the estrogen receptor 1 gene (ESR1). The effect of these mutations on drug treatment in the protein target encoded by ESR1, namely the estrogen receptor, was achieved via rapid and accurate protein–ligand binding affinity interaction studies which were performed for the selected drugs and the natural ligand estrogen. Four nonsynonymous mutations in the ligand-binding domain were subjected to molecular dynamics simulation using absolute and relative binding free energy methods, leading to the ranking of the efficacy of six selected drugs for patients with the mutations. Our study shows that a personalised clinical decision system can be created by integrating an individual patient’s genomic data at the molecular level within a computational pipeline which ranks the efficacy of binding of particular drugs to variant proteins.</p><h2 dir="ltr">Other Information</h2><p dir="ltr">Published in: Scientific Reports<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41598-021-92785-w" target="_blank">https://dx.doi.org/10.1038/s41598-021-92785-w</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_8def412c5f2a72dd0da92488bf436ce3 |
| identifier_str_mv | 10.1038/s41598-021-92785-w |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/31444714 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | The effect of protein mutations on drug binding suggests ensuing personalised drug selectionShunzhou Wan (1361247)Deepak Kumar (63095)Valentin Ilyin (2368732)Ussama Al Homsi (14442150)Gulab Sher (12984698)Alexander Knuth (11104)Peter V. Coveney (418676)Biological sciencesGeneticsBiomedical and clinical sciencesOncology and carcinogenesisPharmacology and pharmaceutical sciencesBreast cancerGenetics researchMolecular dynamicsMolecular medicineNuclear receptorsPredictive markers<p dir="ltr">The advent of personalised medicine promises a deeper understanding of mechanisms and therefore therapies. However, the connection between genomic sequences and clinical treatments is often unclear. We studied 50 breast cancer patients belonging to a population-cohort in the state of Qatar. From Sanger sequencing, we identified several new deleterious mutations in the estrogen receptor 1 gene (ESR1). The effect of these mutations on drug treatment in the protein target encoded by ESR1, namely the estrogen receptor, was achieved via rapid and accurate protein–ligand binding affinity interaction studies which were performed for the selected drugs and the natural ligand estrogen. Four nonsynonymous mutations in the ligand-binding domain were subjected to molecular dynamics simulation using absolute and relative binding free energy methods, leading to the ranking of the efficacy of six selected drugs for patients with the mutations. Our study shows that a personalised clinical decision system can be created by integrating an individual patient’s genomic data at the molecular level within a computational pipeline which ranks the efficacy of binding of particular drugs to variant proteins.</p><h2 dir="ltr">Other Information</h2><p dir="ltr">Published in: Scientific Reports<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41598-021-92785-w" target="_blank">https://dx.doi.org/10.1038/s41598-021-92785-w</a></p>2021-06-29T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41598-021-92785-whttps://figshare.com/articles/journal_contribution/The_effect_of_protein_mutations_on_drug_binding_suggests_ensuing_personalised_drug_selection/31444714CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/314447142021-06-29T09:00:00Z |
| spellingShingle | The effect of protein mutations on drug binding suggests ensuing personalised drug selection Shunzhou Wan (1361247) Biological sciences Genetics Biomedical and clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences Breast cancer Genetics research Molecular dynamics Molecular medicine Nuclear receptors Predictive markers |
| status_str | publishedVersion |
| title | The effect of protein mutations on drug binding suggests ensuing personalised drug selection |
| title_full | The effect of protein mutations on drug binding suggests ensuing personalised drug selection |
| title_fullStr | The effect of protein mutations on drug binding suggests ensuing personalised drug selection |
| title_full_unstemmed | The effect of protein mutations on drug binding suggests ensuing personalised drug selection |
| title_short | The effect of protein mutations on drug binding suggests ensuing personalised drug selection |
| title_sort | The effect of protein mutations on drug binding suggests ensuing personalised drug selection |
| topic | Biological sciences Genetics Biomedical and clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences Breast cancer Genetics research Molecular dynamics Molecular medicine Nuclear receptors Predictive markers |