Uncovering the Mechanism of Drug Resistance Caused by the T790M Mutation in EGFR Kinase From Absolute Binding Free Energy Calculations
The emergence of drug resistance may increase the death rates in advanced non-small cell lung cancer (NSCLC) patients. The resistance of erlotinib, the effective first-line antitumor drug for NSCLC with the L858R mutation of epidermal growth factor receptor (EGFR), happens after the T790M mutation o...
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| Format: | Article |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.922839/full |
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| author | Huaxin Zhou Huaxin Zhou Haohao Fu Haohao Fu Han Liu Han Liu Xueguang Shao Xueguang Shao Wensheng Cai Wensheng Cai |
| author_facet | Huaxin Zhou Huaxin Zhou Haohao Fu Haohao Fu Han Liu Han Liu Xueguang Shao Xueguang Shao Wensheng Cai Wensheng Cai |
| author_sort | Huaxin Zhou |
| collection | DOAJ |
| description | The emergence of drug resistance may increase the death rates in advanced non-small cell lung cancer (NSCLC) patients. The resistance of erlotinib, the effective first-line antitumor drug for NSCLC with the L858R mutation of epidermal growth factor receptor (EGFR), happens after the T790M mutation of EGFR, because this mutation causes the binding of adenosine triphosphate (ATP) to EGFR more favorable than erlotinib. However, the mechanism of the enhancement of the binding affinity of ATP to EGFR, which is of paramount importance for the development of new inhibitors, is still unclear. In this work, to explore the detailed mechanism of the drug resistance due to the T790M mutation, molecular dynamics simulations and absolute binding free energy calculations have been performed. The results show that the binding affinity of ATP with respect to the L858R/T790M mutant is higher compared with the L858R mutant, in good agreement with experiments. Further analysis demonstrates that the T790M mutation significantly changes the van der Waals interaction of ATP and the binding site. We also find that the favorable binding of ATP to the L858R/T790M mutant, compared with the L858R mutant, is due to a conformational change of the αC-helix, the A-loop and the P-loop of the latter induced by the T790M mutation. This change makes the interaction of ATP and P-loop, αC-helix in the L858R/T790M mutant higher than that in the L858R mutant, therefore increasing the binding affinity of ATP to EGFR. We believe the drug-resistance mechanism proposed in this study will provide valuable guidance for the design of drugs for NSCLC. |
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| language | English |
| last_indexed | 2024-04-13T14:18:59Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-a0e52331ca71433daf59126f1e4644e12022-12-22T02:43:33ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-05-01910.3389/fmolb.2022.922839922839Uncovering the Mechanism of Drug Resistance Caused by the T790M Mutation in EGFR Kinase From Absolute Binding Free Energy CalculationsHuaxin Zhou0Huaxin Zhou1Haohao Fu2Haohao Fu3Han Liu4Han Liu5Xueguang Shao6Xueguang Shao7Wensheng Cai8Wensheng Cai9Research Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, ChinaHaihe Laboratory of Sustainable Chemical Transformations, Tianjin, ChinaResearch Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, ChinaHaihe Laboratory of Sustainable Chemical Transformations, Tianjin, ChinaResearch Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, ChinaHaihe Laboratory of Sustainable Chemical Transformations, Tianjin, ChinaResearch Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, ChinaHaihe Laboratory of Sustainable Chemical Transformations, Tianjin, ChinaResearch Center for Analytical Sciences, Frontiers Science Center for New Organic Matter, College of Chemistry, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, ChinaHaihe Laboratory of Sustainable Chemical Transformations, Tianjin, ChinaThe emergence of drug resistance may increase the death rates in advanced non-small cell lung cancer (NSCLC) patients. The resistance of erlotinib, the effective first-line antitumor drug for NSCLC with the L858R mutation of epidermal growth factor receptor (EGFR), happens after the T790M mutation of EGFR, because this mutation causes the binding of adenosine triphosphate (ATP) to EGFR more favorable than erlotinib. However, the mechanism of the enhancement of the binding affinity of ATP to EGFR, which is of paramount importance for the development of new inhibitors, is still unclear. In this work, to explore the detailed mechanism of the drug resistance due to the T790M mutation, molecular dynamics simulations and absolute binding free energy calculations have been performed. The results show that the binding affinity of ATP with respect to the L858R/T790M mutant is higher compared with the L858R mutant, in good agreement with experiments. Further analysis demonstrates that the T790M mutation significantly changes the van der Waals interaction of ATP and the binding site. We also find that the favorable binding of ATP to the L858R/T790M mutant, compared with the L858R mutant, is due to a conformational change of the αC-helix, the A-loop and the P-loop of the latter induced by the T790M mutation. This change makes the interaction of ATP and P-loop, αC-helix in the L858R/T790M mutant higher than that in the L858R mutant, therefore increasing the binding affinity of ATP to EGFR. We believe the drug-resistance mechanism proposed in this study will provide valuable guidance for the design of drugs for NSCLC.https://www.frontiersin.org/articles/10.3389/fmolb.2022.922839/fullabsolute binding free energy calculationEpidermal Growth Factor Receptor (EGFR)T790M mutationdrug resistancemolecular dynamics simulationBFEE2 |
| spellingShingle | Huaxin Zhou Huaxin Zhou Haohao Fu Haohao Fu Han Liu Han Liu Xueguang Shao Xueguang Shao Wensheng Cai Wensheng Cai Uncovering the Mechanism of Drug Resistance Caused by the T790M Mutation in EGFR Kinase From Absolute Binding Free Energy Calculations Frontiers in Molecular Biosciences absolute binding free energy calculation Epidermal Growth Factor Receptor (EGFR) T790M mutation drug resistance molecular dynamics simulation BFEE2 |
| title | Uncovering the Mechanism of Drug Resistance Caused by the T790M Mutation in EGFR Kinase From Absolute Binding Free Energy Calculations |
| title_full | Uncovering the Mechanism of Drug Resistance Caused by the T790M Mutation in EGFR Kinase From Absolute Binding Free Energy Calculations |
| title_fullStr | Uncovering the Mechanism of Drug Resistance Caused by the T790M Mutation in EGFR Kinase From Absolute Binding Free Energy Calculations |
| title_full_unstemmed | Uncovering the Mechanism of Drug Resistance Caused by the T790M Mutation in EGFR Kinase From Absolute Binding Free Energy Calculations |
| title_short | Uncovering the Mechanism of Drug Resistance Caused by the T790M Mutation in EGFR Kinase From Absolute Binding Free Energy Calculations |
| title_sort | uncovering the mechanism of drug resistance caused by the t790m mutation in egfr kinase from absolute binding free energy calculations |
| topic | absolute binding free energy calculation Epidermal Growth Factor Receptor (EGFR) T790M mutation drug resistance molecular dynamics simulation BFEE2 |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.922839/full |
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