A comprehensive high-throughput screening approach for discovering inhibitors targeting the menin-MLL1 interaction.

Abstract

The prognosis for mixed-lineage leukemia (MLL), particularly in young children, remains a significant health concern due to the limited therapeutic options available. MLL refers to KMT2A chromosomal translocations that produce MLL fusion proteins. The protein menin, which is essential for the malignant potential of these MLL fusion proteins, offers novel targets for acute leukemia treatment. This study reports the identification of potential new inhibitors of MLL-mediated leukemia targeting menin through the screening of two distinct drug libraries and existing inhibitors. The 3D structure of the protein was retrieved from the Protein Data Bank (ID: 8IG0). The drug libraries, sourced from public repositories such as the 'Epigenetic Drug Library' and 'The FDA-anticancer Drug Library,' yielded top candidates like Tozaseritib and Panobinostat, which exhibited the highest binding energy scores in the Glide virtual screening module. Additionally, 31 known menin-MLL1 inhibitors were identified through PDB screening and subsequently docked with the menin protein. The top three inhibitors (M-525, M-808, and MI-89) were selected for further analysis. Five menin-ligand complexes were validated using molecular dynamics analysis and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations to verify the stability and binding mechanisms.These findings provide insights into the molecular mechanisms of these drugs and lay the groundwork for future clinical development aimed at improving outcomes for acute myeloid leukemia (AML) patients.