Targeting Acute Myeloid Leukemia with 1,2,4-triazolo[4,3-b]pyridazine derivatives: a molecular docking, dynamics, and ADMET approach

Abstract

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. Graphical abstract

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