The Structural Effect of FLT3 Mutations at 835th Position and Their Interaction with Acute Myeloid Leukemia Inhibitors: In Silico Approach
Copyright policy )The Structural Effect of FLT3 Mutations at 835th Position and Their Interaction with Acute Myeloid Leukemia Inhibitors: In Silico Approach
FMS-like tyrosine kinase 3 (FLT3) gene mutations have been found in more than one-third of Acute Myeloid Leukemia (AML) cases. The most common point mutation in FLT3 occurs at the 835th residue (D835A/E/F/G/H/I/N/V/Y), in the activation loop region. The D835 residue is critical in maintaining FLT3 inactive conformation; these mutations might influence the interaction with clinically approved AML inhibitors used to treat the AML. The molecular mechanism of each of these mutations and their interactions with AML inhibitors at the atomic level is still unknown. In this manuscript, we have investigated the structural consequence of native and mutant FLT-3 proteins and their molecular mechanisms at the atomic level, using molecular dynamics simulations (MDS). In addition, we use the molecular docking method to investigate the binding pattern between the FLT-3 protein and AML inhibitors upon mutations. This study apparently elucidates that, due to mutations in the D835, the FLT-3 structure loses its conformation and becomes more flexible compared to the native FLT3 protein. These structural changes are suggested to contribute to the relapse and resistance responses to AML inhibitors. Identifying the effects of FLT3 at the molecular level will aid in developing a personalized therapeutic strategy for treating patients with FLT-3-associated AML.
- Imam Abdulrahman Bin Faisal University Saudi Arabia
Protein Conformation, leukemia, interaction, Molecular Dynamics Simulation, mutations, Polymorphism, Single Nucleotide, Article, Molecular Docking Simulation, flexibility, Leukemia, Myeloid, Acute, AML, fms-Like Tyrosine Kinase 3, Drug Resistance, Neoplasm, inhibitors, Mutation, Humans, Point Mutation, Computer Simulation, FLT3, Protein Kinase Inhibitors
Protein Conformation, leukemia, interaction, Molecular Dynamics Simulation, mutations, Polymorphism, Single Nucleotide, Article, Molecular Docking Simulation, flexibility, Leukemia, Myeloid, Acute, AML, fms-Like Tyrosine Kinase 3, Drug Resistance, Neoplasm, inhibitors, Mutation, Humans, Point Mutation, Computer Simulation, FLT3, Protein Kinase Inhibitors
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