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The effect of protein mutations on drug binding suggests ensuing personalised drug selection

Wan, S; Kumar, D; Ilyin, V; Al Homsi, U; Sher, G; Knuth, A; Coveney, PV; (2021) The effect of protein mutations on drug binding suggests ensuing personalised drug selection. Scientific Reports , 11 (1) , Article 13452. 10.1038/s41598-021-92785-w. Green open access

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Abstract

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.

Type: Article
Title: The effect of protein mutations on drug binding suggests ensuing personalised drug selection
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41598-021-92785-w
Publisher version: https://doi.org/10.1038/s41598-021-92785-w
Language: English
Additional information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10131155
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