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.

Autor:	Suriñach A; Nostrum Biodiscovery, Av. Josep Tarradellas 8-10, 08029 Barcelona, Spain., Hospital A; Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona 08028, Spain., Westermaier Y; Nostrum Biodiscovery, Av. Josep Tarradellas 8-10, 08029 Barcelona, Spain., Jordà L; Barcelona Supercomputing Center (BSC), Plaça Eusebi Güell, 1-3, Barcelona 08034, Spain., Orozco-Ruiz S; Barcelona Supercomputing Center (BSC), Plaça Eusebi Güell, 1-3, Barcelona 08034, Spain., Beltrán D; Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona 08028, Spain., Colizzi F; Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona 08028, Spain., Andrio P; Barcelona Supercomputing Center (BSC), Plaça Eusebi Güell, 1-3, Barcelona 08034, Spain., Soliva R; Nostrum Biodiscovery, Av. Josep Tarradellas 8-10, 08029 Barcelona, Spain., Municoy M; Nostrum Biodiscovery, Av. Josep Tarradellas 8-10, 08029 Barcelona, Spain., Gelpí JL; Barcelona Supercomputing Center (BSC), Plaça Eusebi Güell, 1-3, Barcelona 08034, Spain.; Department Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona 08029, Spain., Orozco M; Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona 08028, Spain.; Department Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona 08029, Spain.
Jazyk:	angličtina
Zdroj:	Journal of chemical information and modeling [J Chem Inf Model] 2023 Jan 09; Vol. 63 (1), pp. 321-334. Date of Electronic Publication: 2022 Dec 28.
DOI:	10.1021/acs.jcim.2c01344
Abstrakt:	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.
Databáze:	MEDLINE
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