As a potent and selective drug, brigatinib exhibits high efficacy against 
wild-type and mutant anaplastic lymphoma kinase (ALK) proteins to treat 
non-small cell lung cancer. In this work, the mechanisms of brigatinib binding 
to wild type and four mutant ALKs were investigated to gain insight into the 
dynamic energetic and structural information with respect to the design of novel 
inhibitors. Comparison between ALK-brigatinib and ALK-crizotinib suggests that 
the scaffold of brigatinib is well anchored to the residue Met1199 of hinge 
region by two hydrogen bonds, and the residue Lys1150 has the strong 
electrostatic interaction with the dimethylphosphine oxide moiety in brigatinib. 
These ALK mutations have significant influences on the flexibility of P-loop 
region and DFG sequences, but do not impair the hydrogen bonds between 
brigatinib and the residue Met1199 of hinge region. And mutations (L1196M, 
G1269A, F1174L, and R1275Q) induce diverse conformational changes of brigatinib 
and the obvious energy variation of residues Glu1167, Arg1209, Asp1270, and 
Asp1203. Together, the detailed explanation of mechanisms of those mutations 
with brigatinib further provide several guidelines for the development of more 
effective ALK inhibitors.