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- W4283643314 endingPage "105787" @default.
- W4283643314 startingPage "105787" @default.
- W4283643314 abstract "Mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR), including L858R/T790M double and L858R/T790M/C797S triple mutations, are major causes of acquired resistance towards EGFR targeted drugs. In this work, a combination of comprehensive molecular modeling and in vitro kinase inhibition assay was used to unravel the mutational effects of EGFR on the susceptibility of three generations of EGFR tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) in comparison with the wild-type EGFR. The binding affinity of all studied inhibitors towards the double and triple EGFR mutations was in good agreement with the experimental data, ranked in the order of osimertinib > afatinib > dacomitinib > erlotinib > gefitinib. Three hot-spot residues at the hinge region (M790, M793, and C797) were involved in the binding of osimertinib and afatinib, enhancing their inhibitory activity towards mutated EGFRs. Both double and triple EGFR mutations causing erlotinib and gefitinib resistance are mainly caused by the low number of H-bond occupations, the low number of surrounding atoms, and the high number of water molecules accessible to the enzyme active site. According to principal component analysis, the molecular complexation of osimertinib against the two mutated EGFRs was in a closed conformation, whereas that against wild-type EGFR was in an open conformation, resulting in drug resistance. This work paves the way for further design of the novel EGFR inhibitors to overcome drug resistance mechanisms." @default.
- W4283643314 created "2022-06-29" @default.
- W4283643314 creator A5016779703 @default.
- W4283643314 creator A5027050921 @default.
- W4283643314 creator A5031067302 @default.
- W4283643314 creator A5041008389 @default.
- W4283643314 creator A5082847062 @default.
- W4283643314 date "2022-08-01" @default.
- W4283643314 modified "2023-10-06" @default.
- W4283643314 title "Structural dynamics and kinase inhibitory activity of three generations of tyrosine kinase inhibitors against wild-type, L858R/T790M, and L858R/T790M/C797S forms of EGFR" @default.
- W4283643314 cites W1565276921 @default.
- W4283643314 cites W1608710587 @default.
- W4283643314 cites W1691796058 @default.
- W4283643314 cites W1964321121 @default.
- W4283643314 cites W1968984443 @default.
- W4283643314 cites W1970580490 @default.
- W4283643314 cites W1976427666 @default.
- W4283643314 cites W1976499671 @default.
- W4283643314 cites W1989173185 @default.
- W4283643314 cites W1992687322 @default.
- W4283643314 cites W2003984225 @default.
- W4283643314 cites W2004822259 @default.
- W4283643314 cites W2007649418 @default.
- W4283643314 cites W2012500759 @default.
- W4283643314 cites W2016408686 @default.
- W4283643314 cites W2018917333 @default.
- W4283643314 cites W2020988380 @default.
- W4283643314 cites W2025768791 @default.
- W4283643314 cites W2036785342 @default.
- W4283643314 cites W2042278676 @default.
- W4283643314 cites W2049484790 @default.
- W4283643314 cites W2050211354 @default.
- W4283643314 cites W2052035095 @default.
- W4283643314 cites W2057069307 @default.
- W4283643314 cites W2057166163 @default.
- W4283643314 cites W2057811812 @default.
- W4283643314 cites W2066314848 @default.
- W4283643314 cites W2071794983 @default.
- W4283643314 cites W2075962297 @default.
- W4283643314 cites W2088540000 @default.
- W4283643314 cites W2093379071 @default.
- W4283643314 cites W2097767970 @default.
- W4283643314 cites W2097781997 @default.
- W4283643314 cites W2097817246 @default.
- W4283643314 cites W2097980962 @default.
- W4283643314 cites W2106140689 @default.
- W4283643314 cites W2109080255 @default.
- W4283643314 cites W2109480388 @default.
- W4283643314 cites W2110841878 @default.
- W4283643314 cites W2118375252 @default.
- W4283643314 cites W2119248047 @default.
- W4283643314 cites W2120718661 @default.
- W4283643314 cites W2123681603 @default.
- W4283643314 cites W2127044379 @default.
- W4283643314 cites W2129360604 @default.
- W4283643314 cites W2132540363 @default.
- W4283643314 cites W2133051701 @default.
- W4283643314 cites W2133963438 @default.
- W4283643314 cites W2138297714 @default.
- W4283643314 cites W2138536086 @default.
- W4283643314 cites W2146418087 @default.
- W4283643314 cites W2147993766 @default.
- W4283643314 cites W2151120050 @default.
- W4283643314 cites W2152905269 @default.
- W4283643314 cites W2161682775 @default.
- W4283643314 cites W2169816570 @default.
- W4283643314 cites W2170552969 @default.
- W4283643314 cites W2278324600 @default.
- W4283643314 cites W2279058190 @default.
- W4283643314 cites W2332712348 @default.
- W4283643314 cites W2404280981 @default.
- W4283643314 cites W2476256861 @default.
- W4283643314 cites W2509808024 @default.
- W4283643314 cites W2556130581 @default.
- W4283643314 cites W2593028314 @default.
- W4283643314 cites W2605979374 @default.
- W4283643314 cites W2608834008 @default.
- W4283643314 cites W2768078998 @default.
- W4283643314 cites W2770828094 @default.
- W4283643314 cites W2782438044 @default.
- W4283643314 cites W2782884792 @default.
- W4283643314 cites W2801052665 @default.
- W4283643314 cites W2842012826 @default.
- W4283643314 cites W2886368623 @default.
- W4283643314 cites W2907478003 @default.
- W4283643314 cites W2917344804 @default.
- W4283643314 cites W2917837889 @default.
- W4283643314 cites W2924740051 @default.
- W4283643314 cites W2945828093 @default.
- W4283643314 cites W2947959828 @default.
- W4283643314 cites W2985936655 @default.
- W4283643314 cites W2988192292 @default.
- W4283643314 cites W2998884981 @default.
- W4283643314 cites W3012576274 @default.
- W4283643314 cites W3036012327 @default.
- W4283643314 cites W3046944605 @default.
- W4283643314 cites W3091019682 @default.
- W4283643314 cites W3095760404 @default.