Exploring EZH2-Proteasome Dual-Targeting: A Computational Strategy to Combat Multiple Myeloma

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase, its overexpressed in multiple myeloma (MM) and plays a role in drug resistance. Proteasome is also a key target in MM. MM had no cure until recently, it still has problems with drug resistance. These targets have common pathways making them promising targets for a dual inhibiting strategy. We devised a computational strategy to identify EZH2 and 20S proteasome dual inhibitors. So, known ligands for each protein were employed in docking studies against both proteins, their bioactivity data were used to develop models to choose the best compounds. The top candidates were those with residue interaction patterns like those of co-crystal ligands. Machine learning models, classification decision trees, were used to investigate the characteristics that make a ligand active in each target. Molecular dynamics simulations were performed with the top candidates from molecular docking. Two potential hit compounds were identified.