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 the electrostatic interaction and SASA, which were allosterically regulated by residues Glu-661 and Asp-829. When FLT3-F691L was bound to quizartinib, a large conformational change was observed via combination of accelerated MD simulations (aMDs), principal component analysis (PCA), and free energy landscape (FEL) calculations. The umbrella sampling (US) simulations were applied to investigate the dissociation processes of the quizartinib or PLX3397 from FLT3-WT and FLT3-F691L. The calculated results suggested that PLX3397 had similar dissociation processes from both FLT3-WT and FLT3-F691L, but quizartinib dissociated more easily from FLT3-F691L than from FLT3-WT. Thus, reduced residence time was responsible for the FLT3-F691L resistance to inhibitors. These findings indicated that both the conformational changes of αC-helix and A-loop and the drug residence time should be considered in the design of drugs so that rational decisions can be made to overcome resistance to FLT3-F691L.

3D-QSAR and Molecular Dynamics Study of Isoxazole Derivatives to Identify the Structural Requirements for Farnesoid X Receptor (FXR) Agonists

“…The parentheses show the average of all structures sampled on the MD trajectory. The dynamic cross-correlation matrix (DCCM) was used to identify the cross-correlation shifts of the backbone atoms and to show protein backbone conformation shifts, and was performed using RStudio software (version 4.3.1) and the Bio3d application [ 75 , 76 , 77 ]. The cross-correlation coefficient value fluctuated from −1 to 1, and the resulting dynamic cross-correlation matrices displayed amino acids that have both positive and negative effects.…”

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

“…In contrast, there was no significant difference between the dissociation processes of WT-FLT3 and FLT3-F691L from PLX3397. 138 D835F and Y842H mutations in TKD were thought to make quizartinib and sorafenib ineffective. 51 , 139 In a particular study, multiple simulations of WT- and mutant (D835F, Y842H) FLT3 in drug-bound, drug-free, inactive or active forms were investigated.…”