Rational design and comparative docking and simulation of modified FLT3 inhibitors: a study on enhanced binding...

FLT3 is a critical therapeutic target for acute myeloid leukemia (AML), and its inhibition remains a key strategy in AML management. In this study, we optimized the known compound CHEMBL4444839 to design a novel analogue, CHEMBL4444839-Analogue, showing improved pharmacological and structural characteristics. Pharmacokinetic profiling evaluation revealed that the analogue had enhanced drug-likeness, metabolic stability, and intestinal permeability, along with reduced predicted toxicity. Molecular docking revealed that CHEMBL4444839-Analogue exhibited a binding energy of -10.4 kcal/mol versus -8.7 kcal/mol for the parent compound, forming additional hydrogen bonds and hydrophobic contacts with GLU661, CYS694, LEU818, and PHE830 in the ATP binding pocket. Molecular dynamics simulation over 100 ns demonstrated lower average RMSD (1.78 Å vs 2.34 Å) and reduced RMSF fluctuations at the activation loop and DFG-out region, indicating enhanced conformational stability. Free energy calculations confirmed higher thermodynamic stability of the analogue versus CHEMBL4444839. The analogue also restricted domain motion and improved residue correlation, indicating better stabilization of FLT3 in its inactive conformation. Incorporation of a fluorocyclobutane moiety significantly contributed to enhanced rigidity and optimized interaction geometry, collectively establishing CHEMBL4444839-Analogue as a more promising and selective FLT3 inhibitor for AML therapy.

Docking of CHEMBL4444839 and its designed analogue was performed to analyze binding interactions and guide structural modifications. Pharmacokinetic and toxicity parameters were predicted using SwissADME, ADMETlab 2.0, and ProTox-II. Molecular dynamics simulations were executed with GROMACS 2023 using the CHARMM36 force field to assess conformational stability, followed by MM-PBSA and dynamic cross-correlation analyses. The integrated computational results demonstrated that CHEMBL4444839-Analogue achieved stronger binding affinity, reduced flexibility, and superior stability compared to the parent molecule, validating its potential as an optimized FLT3 inhibitor candidate for further biochemical and therapeutic evaluation.