Discovering potential inhibitors of the YEATS domain of YEATS2 through virtual screening, molecular optimization and molecular dynamics simulations

Abstract

YEATS domains have been recently identified as novel readers of histone lysine acylation. Increasing evidence has revealed that dysregulated interactions between YEATS domains and histone lysine acylation are associated with human disease, suggesting the therapeutic potential of YEATS domain inhibition. The inhibitors targeting the YEATS domains of AF9, ENL, and GAS41 have been developed, while the YEATS2 YEATS domain inhibitors have not been reported so far. In this study, we have identified potential YEATS2 YEATS domain inhibitor candidates by integrating multiple computational approaches. Structure-based and ligand-based virtual screening was performed, and a total of 101 small molecule ligands were found from ZINC Natural Products, Enamine Advanced and Enamine HTS with affinity >−8.5 kcal mol⁻¹. Structure-based drug design (SBDD) and ligand-based drug design (LBDD) strategies were used to conduct three rounds of molecular optimization based on the interaction between the small molecule ligands and the YEATS2 YEATS domain, and three groups of optimized molecules with better binding affinity were finally selected. The optimized compounds op2-1, op2-6, op3-5, and op3-6 were selected for molecular dynamics (MD) simulation studies to examine the interaction and stability of the best predicted conformation of the protein–ligand complex (MM/GBSA, −49.85 to −73.21 kcal mol⁻¹). This study identifies the dominant molecular fragments and interaction modes that bind to various parts of the YEATS2 YEATS domain. Taken together, our study provides a starting platform for the development of highly active and selective inhibitors for the YEATS2 YEATS domain and the study of their mechanism of action in the future.