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 8f, 8j, 8k, and 8l as promising candidates, with 8l exhibiting the most favorable binding free energy (ΔG(bind) = - 58.96 kcal/mol). Docking-derived inhibition constants (Ki) revealed that 8f, 8j, 8k, and 8l had Ki values of 0.31 µM, 0.32 µM, 0.35 µM, and 0.34 µM, respectively, while Sunitinib showed a slightly weaker Ki 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 (8j), compared to the unbound APO structure (2.12 Å). Compound 8l 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 8l potent anti-AML activity (IC₅₀ = 1.5 µM), ADMET predictions revealed pharmacokinetic limitations, including low solubility and permeability. These findings position compound 8l 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00418-1.