In silico screening of a designed focused chemical space identifies novel alkyl hydrazides as potent HDAC11 inhibitors

The therapeutic potential of HDAC inhibitors containing a hydroxamic acid moiety as a zinc-binding group (ZBG) is limited in clinical use due to their potential mutagenicity. In addition, hydroxamic acids often exhibit off-target effects that can lead to undesirable toxicity. Therefore, the development of HDAC inhibitors with alternative ZBGs has proven to be a promising approach to overcome these drawbacks. HDAC inhibitors carrying alkyl hydrazide as ZBG have recently been published as selective inhibitors for different HDAC subtypes. In the present study, a ligand-based virtual screening workflow, employing a classification categorical model, was developed and applied for a designed targeted chemical space. The two most promising hits from the virtual screening were synthesized and evaluated by in vitro enzyme inhibition assays. Both hits showed strong inhibition of HDAC11 with IC₅₀ values in the nanomolar range. In addition, the compounds showed good selectivity towards HDAC11 at a concentration of 1 μM, only HDAC8 was also significantly inhibited among all tested subtypes. Finally, the binding mode of the selected candidates was investigated by docking against different HDACs, followed by molecular dynamics simulations and metadynamics studies to provide insights for further chemical optimization.

Alkyl hydrazides; AlphaFold; Classification model; Docking; HDAC11; Molecular dynamics simulation; Virtual screening.