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Melanoma inhibitor of apoptosis protein (ML-IAP) is an IAP family member involved in tumour cell survival and a potential target in ML-IAP-expressing leukaemia. Here, 59 319 tetrapeptides were screened against ML-IAP by molecular docking, and four top-ranked peptides were selected. Microscale thermophoresis confirmed binding of peptides 1-4 to ML-IAP, with peptide-1 showing the lowest K_d value and a lower K_d value than the Smac peptide. Structure-activity relationship (SAR) analysis indicated that peptide-1 had more favourable ML-IAP recognition features. A molecular dynamics simulation, molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) calculations and free-energy landscape analysis supported the relative conformational stability of the ML-IAP-peptide-1 complex. MTT assays showed that peptide-1 inhibited MOLT-4, MOLM-13, and MV-4-11 cell proliferation, with limited inhibitory activity against HS-27A cells. ML-IAP knockdown reduced peptide-1 activity, while peptide-1 increased the cleaved/total caspase-3 ratio and altered Bax and Bcl-2 mRNA expression. These results suggest that peptide-1 may represent an ML-IAP-targeting peptide with antiproliferative activity in leukaemia cells.