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High-Throughput Prediction of the Impact of Genetic Variability on Drug Sensitivity and Resistance Patterns for Clinically Relevant Epidermal Growth Factor Receptor Mutations from Atomistic Simulations.pdf (9.97 MB)

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2022-12-28

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/192069

High-Throughput Prediction of the Impact of Genetic Variability on Drug Sensitivity and Resistance Patterns for Clinically Relevant Epidermal Growth Factor Receptor Mutations from Atomistic Simulations

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Recurs relacionat

https://doi.org/10.1021/acs.jcim.2c01344

Resum

Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) can be drivers of cancer and also trigger drug resistance in patients receiving chemotherapy treatment based on kinase inhibitors. A priori knowledge of the impact of EGFR variants on drug sensitivity would help to optimize chemotherapy and design new drugs that are effective against resistant variants before they emerge in clinical trials. To this end, we explored a variety of in silico methods, from sequence-based to "state-of-the-art" atomistic simulations. We did not find any sequence signal that can provide clues on when a drug-related mutation appears or the impact of such mutations on drug activity. Low-level simulation methods provide limited qualitative information on regions where mutations are likely to cause alterations in drug activity, and they can predict around 70% of the impact of mutations on drug efficiency. High-level simulations based on nonequilibrium alchemical free energy calculations show predictive power. The integration of these "state-of-the-art" methods into a workflow implementing an interface for parallel distribution of the calculations allows its automatic and high-throughput use, even for researchers with moderate experience in molecular simulations.

Matèries

Resistència als medicaments, Càncer, Quimioteràpia, Genètica

Matèries (anglès)

Drug resistance, Cancer, Chemotherapy, Genetics

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Col·leccions

Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

Citació

SURIÑACH, Aristarc, HOSPITAL GASCH, Adam, WESTERMAIER, Yvonne, JORDÀ BORDOY, Luis, OROZCO RUIZ, Sergi, BELTRÁN, Daniel, COLIZZI, Francesco, ANDRIO, Pau, SOLIVA, Robert, MUNICOY, Martí, GELPI BUCHACA, Josep lluís, OROZCO LÓPEZ, Modesto. High-Throughput Prediction of the Impact of Genetic Variability on Drug Sensitivity and Resistance Patterns for Clinically Relevant Epidermal Growth Factor Receptor Mutations from Atomistic Simulations. _Journal of Chemical Information and Modeling_. 2023. Vol. 63, núm. 1, pàgs. 321-334. [consulta: 22 de gener de 2026]. ISSN: 1549-9596. [Disponible a: https://hdl.handle.net/2445/192069]

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