Molecular modeling and design of selective histone deacetylase 11 (HDAC11) inhibitors

Abstract

Histone deacetylase 11 (HDAC11) has emerged as an interesting target for potential treatment of various diseases including cancer and metabolic diseases. This work focuses on the modelling, design and development of novel selective HDAC11 inhibitors. Since there are no crystal structures for HDAC11 reported so far, an AlphaFold2 model of HADC11 was optimized and used to study the reported HDAC11 inhibitors. The optimized model was used in a virtual screening workflow to identify new selective ligand. Furthermore, the model was employed for the structure-based design of novel selective inhibitor. The deigned and the identified compounds were synthesized and showed promising activity and selectivity. Finally, a ligand-based virtual screening workflow employing a classification model was developed and applied to identify potential HDAC11 inhibitors.