In-silico assessment of structure-based derivatives of phytochemicals from CHEESE webserver for anti-EZH2: advancing druggable lead identification for pancreatic cancer therapy

Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator implicated in various cancers, making it an attractive target for therapeutic intervention. In this study, we employed a structure-based drug discovery approach to identify and evaluate phytochemical derivatives for their potential to bind EZH2. Using the CHEESE webserver, five phytochemicals, namely Moracin P, Naringenin 5-rhamnoside, Pinostrobin 5-O-Glucoside, Phytocassane A, and Sakuranin with best performance against EZH2-PPARs from our previous study was used to generate top ten new derivatives each. The identified derivatives were subjected to molecular docking, pharmacokinetic, and toxicity predictions. The complexes of the top-performing compounds with EZH2 were further subjected to a 200 ns molecular dynamics simulation (MDS). Molecular docking results revealed that several derivatives of Moracin P, Naringenin 5-rhamnoside, and Phytocassane A displayed higher predicted binding affinities compared to the parent template previously assessed for EZH2, engaging critical residues through hydrogen bonds and hydrophobic interactions. ADMET profiling indicated favorable pharmacokinetic and toxicity properties, with selected compounds meeting key drug-likeness criteria. MDS over 200 ns further confirmed the stability of selected protein-ligand complexes, with Moracin_P7 and Pinostrobin 5-O-Glucoside_5 exhibiting high degrees of stability, while contact analysis highlighted consistent interactions with the active site residues. Conclusively, these findings further provide evidence for the potential of phytochemical derivative as promising EZH2 inhibitors and laying the groundwork for further in-vitro and in-vivo validation.