Insights Into the Resistance Mechanisms of Inhibitors to FLT3 F691L Mutation via an Integrated Computational Approach.

ABSTRACT: Research has shown that FMS-like tyrosine kinase 3 (FLT3) may be a vital drug target for acute myeloid leukemia (AML). However, even though the clinically relevant F691L gatekeeper mutation conferred resistance to current FLT3 drug quizartinib, PLX3397 remained unaffected. In this study, the protein-ligand interactions between FLT3 kinase domain (wild-type or F691L) and quizartinib or PLX3397 were compared via an integrated computational approach. The classical molecular dynamics (MD) simulations in conjunction with dynamic cross-correlation (DCC) analysis, solvent-accessible surface area (SASA), and free energy calculations indicated that the resistant mutation may induce the conformational change of αC-helix and A-loop of the FLT3 protein. The major variations were controlled by t

SUBMITTER: Sun Y 

PROVIDER: S-EPMC6763581 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature