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

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

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

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.We are indebted to the BioExcel partners, especially Prof. de Groot’s group for helpful discussion on PMX calculations and Prof. Rosa Ma. Badia for help with the PyCOMPSs programming model. This work has been supported by the BioExcel-2: Centre of Excellence for Computational Bio- molecular Research (823830), the Spanish Ministry of Science (RTI2018-096704-B-100 and PID2020-116620GB-I00), and the Instituto de Salud Carlos III−Instituto Nacional de Bioinformática (ISCIII PT 17/0009/0007 cofunded by the Fondo Europeo de Desarrollo Regional). Funding was also provided by the MINECO Severo Ochoa Award of Excellence from the Government of Spain (awarded to IRB Barcelona). M.O. is an ICREA (Institució Catalana de Recerca i Estudis Avancats) Academia researcher. Nostrum Biodiscovery is supported by the Fundación Marcelino Botín (Mind the Gap), CDTI (Neotec grant EXP 00094141/SNEO-20161127), and a Torres Quevedo grant (PTQ2018-009992)Peer Reviewed"Article signat per 12 autors/es: Aristarc Suriñach, Adam Hospital, Yvonne Westermaier, Luis Jordà, Sergi Orozco-Ruiz, Daniel Beltrán, Francesco Colizzi, Pau Andrio, Robert Soliva, Martí Municoy, Josep Lluís Gelpí, and Modesto Orozco*"Postprint (author's final draft