Structure-Guided Discovery and Characterization of Novel FLT3 Inhibitors for Acute Myeloid Leukemia Treatment

FLT3 (FMS-like tyrosine kinase 3), a receptor tyrosine kinase, is frequently mutated in acute myeloid leukemia (AML), a hematologic malignancy marked by aggressive proliferation, poor prognosis, and high relapse rates. Although FDA-approved FLT3 inhibitors exist, their clinical efficacy is often undermined by resistance and off-target effects, underscoring the critical necessity for more effective and selective agents. Here, we employed a structure-based computational approach combining pharmacophore screening via Pharmit and the MolPort compound library to identify novel FLT3 inhibitors. Pharmacophore modeling, virtual screening, and docking identified two promising leads, MolPort-002-705-878 and MolPort-007-550-904, with binding affinities of −11.33 and −10.66 kcal/mol, correspondingly. These compounds were further characterized through molecular dynamics (MD) simulations, incorporating Principal Component Analysis (PCA), free energy landscape (FEL) analysis, density functional theory (DFT) calculations, and ADMET profiling. MD results supported the integrity of the FLT3–lead complexes; DFT revealed favorable reactivity, and ADMET predictions indicated drug-likeness with low toxicity, pending experimental confirmation. This integrated in silico pipeline highlights the potential of these molecules as next-generation FLT3 inhibitors and offers a scalable strategy for targeted AML therapeutics.