期刊
CHEMICAL SCIENCE
卷 9, 期 10, 页码 2740-2749出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c7sc04761d
关键词
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资金
- CCP-BioSim (EPSRC) [EP/M022609/1]
- BBSRC [BB/M000354/1]
- University of Parma
- EPSRC [EP/N018591/1]
- BrisSynBio, a BBSRC/EPSRC Synthetic Biology Research Centre [BB/L01386X/1]
- Biotechnology and Biological Sciences Research Council [BB/L01386X/1, BB/K016601/1, BB/M000354/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/N018591/1, EP/M022609/1, EP/J010588/1, EP/G007705/1] Funding Source: researchfish
- BBSRC [BB/M000354/1, BB/K016601/1, BB/L01386X/1] Funding Source: UKRI
- EPSRC [EP/G007705/1, EP/N018591/1, EP/J010588/1, EP/M022609/1] Funding Source: UKRI
Osimertinib is a third-generation inhibitor approved for the treatment of non-small cell lung cancer. It overcomes resistance to first-generation inhibitors by incorporating an acrylamide group which alkylates Cys797 of EGFR T790M. The mutation of a residue in the P-loop (L718Q) was shown to cause resistance to osimertinib, but the molecular mechanism of this process is unknown. Here, we investigated the inhibitory process for EGFR T790M (susceptible to osimertinib) and EGFR T790M/L718Q (resistant to osimertinib), by modelling the chemical step (i.e., alkylation of Cys797) using QM/MM simulations and the recognition step by MD simulations coupled with free-energy calculations. The calculations indicate that L718Q has a negligible impact on both the activation energy for Cys797 alkylation and the free-energy of binding for the formation of the non-covalent complex. The results show that Gln718 affects the conformational space of the EGFR-osimertinib complex, stabilizing a conformation of acrylamide which prevents reaction with Cys797.
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