Integrated computational and experimental identification of a novel ML-IAP-targeting peptide with antiproliferative activity in leukaemia cells

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 <i>K</i>_d value and a lower <i>K</i>_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.