The Structural Effect of FLT3 Mutations at 835th Position and Their Interaction with Acute Myeloid Leukemia Inhibitors: In Silico Approach

Abstract

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.

Novel potential oncogenic and druggable mutations of FGFRs recur in the kinase domain across cancer types

“…In wild-type FLT3, D835 may stabilize the autoinhibited state by forming interactions with the α-helix, including S838 residue [26]. Mutations at this position lead to increased phosphorylation probably through the destabilization of the autoinhibited conformation [20,27]. A similar mechanism explains the activating nature of the equivalent mutations (D816V/H) in c-KIT receptor [28].…”

Molecular interaction of a putative inhibitor with bacterial SHV, an enzyme associated with antibiotic resistance

“…It was found that the mutation (D8G, S104R and C138Y) in PncA was responsible for rigid binding cavity which in turn abolished conversion of pyrazinamide to its active form and was the reason for pyrazinamide resistance [19]. Similarly, docking and molecular dynamics simulation techniques have been used to study other diseases as well [20][21][22][23]. In the current scenario, artificial intelligence based technologies have started to enter the field of antibiotic design.…”

In Silico-Based Structural Evaluation to Categorize the Pathogenicity of Mutations Identified in the RAD Class of Proteins

“…This study aims at identifying the pathogenicity of such missense mutations using bioinformatics-based approaches. Recent advances in bioinformatics have aided in understanding the fundamentals of genetic makeup, such as the functional impact of amino acid residues on the function and structure of the protein. − These reported deleterious mutations may have a significant impact on the protein’s function. Therefore, it is crucial to identify the pathogenicity of mutations identified in the RAD class of proteins.…”