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The epidermal growth factor receptor （EGFR） family is one kind of tyrosine kinases, also known as ErbBs, they locate at the upstream of RAS/RAF/ERK/MAPK and PI3K/AKT signaling pathways. ErbBs can catalyze the phosphorylation of tyrosine residues, and phosphorylation plays a crucial role in the processes of cells’growth, proliferation and differentiation. We have done some applications of computer aided drug design in EGFR and ErbB2, which have been studied widely as anti-cancer targets.In our study, 22 thiazolo [4,5-d] pyrimidine analogues were docked into the kinase domain of EGFR in order to investigate into the binding recognition mechanism according to the structural and chemical features. It was revealed that there were three binding modes between EGFR and the 22 inhibitors, and the binding sites consisted of three main areas （P1, P2 and P3）. Besides, there was a good linear relationship （R2=0.891） between their -log10IC50 and binding free energy derived from software AutoDock. Importantly, our docking results were confirmed by MD study as robust.We also applied MD and MM/GBSA approach to study T790M of EGFR, one mutation that would lead drug resistance. The results of MM/GBSA calculations showed that T790M led small decrease of affinity of Erlotinib, Lapatinib and AEE788 when binding to EGFR. According to energy decomposition after mutation, Met790 would increase its contribution to the bindings between Erlotinib, Lapatinib, AEE788 and EGFR, respectively. But the T790M would result in conformation and charge distribution changes for small molecules and EGFR, and these changes may decrease residues’contribution to binding, such as Leu718, Cys797, Tyr998 and Met1002. As for Asp800 and Asp855, they would block the bindings because of their large blocking of solvation.Based on EGFR, the 3D structure of ErbB2 was constructed using MODELLER v9.7, and its accuracy was confirmed using MolProbity. Then 14 inhibitors were docked into the kinase domain of ErbB2 in order to find its active sites. Also based on the docking results, MD and MM/GBSA study were applied on ErbB2 in complex with Lapatinib, BMS599626 and inhibitors 25, 27, 32, respectively. The results showed that all the five compounds had high affinity to ErbB2. Through energy decomposition, we learned about the different contributions of these active sites.These conclusions and methods used in the simulation of EGFR and ErbB2 will provide theoretical guide for further study, and help us to design and synthesize novel EGFR, ErbB2 and also EGFR/ErbB2 dual inhibitors.
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