Abstract
Acute Myeloid Leukemia (AML) remains a critical therapeutic challenge, warranting the development of novel inhibitors targeting essential survival proteins such as Myeloid Cell Leukemia-1 (Mcl-1). In this purely computational study, a series of 1,2,4-triazolo[4,3-b]pyridazine derivatives were assessed for their potential as Mcl-1 inhibitors through molecular docking, molecular dynamics (MD) simulations, quantum chemical calculations, and ADMET profiling. Docking identified compounds
,
,
, and
as promising candidates, with
exhibiting the most favorable binding free energy (ΔG
= - 58.96 kcal/mol). Docking-derived inhibition constants (
) revealed that
,
,
, and
had
values of 0.31 µM, 0.32 µM, 0.35 µM, and 0.34 µM, respectively, while Sunitinib showed a slightly weaker
of 0.36 µM. MD simulations demonstrated increased structural stability of the protein-ligand complexes, with RMSD values ranging from 1.68 Å (8f) to 1.90 Å (
), compared to the unbound APO structure (2.12 Å). Compound
maintained a low RMSD (1.71 Å) and favorable flexibility profile (RMSF = 0.89 Å), comparable to Sunitinib (RMSF = 0.76 Å). DFT analysis highlighted 8l's high electronic reactivity, with a HOMO-LUMO gap of 3.18 eV in DMF. Although prior experimental studies confirmed
potent anti-AML activity (IC₅₀ = 1.5 µM), ADMET predictions revealed pharmacokinetic limitations, including low solubility and permeability. These findings position compound
as a compelling lead candidate for AML therapy and provide a strong foundation for future optimization aimed at improving its pharmacokinetic profile and dynamic stability. To substantiate these computational findings, we will initiate experimental validation studies involving Mcl-1 binding assays and cytotoxicity evaluation in AML cell lines.
The online version contains supplementary material available at 10.1007/s40203-025-00418-1.