The chemical tuning of a weak zinc binding motif for histone deacetylase using electronic effects

The hydroxamic acid moiety is an effective metal-binding warhead for a variety of metalloenzyme targets of interest in drug-discovery. For the zinc-containing histone deacetylase enzymes in particular, this chemical group has been widely incorporated and studied in the clinic. An alternative chemical functionality for binding zinc is the α-aminocarbonyl motif, which has been shown to bind to histone deacetylase enzymes. The current article explores the minimal binding site theoretical approach combined with structural knowledge to explore the ideal chemical substitution pattern of the α-aminocarbonyl motif within HDAC8. The metal-binding strength of the group is predicted to be highly tunable to chemical substitution at the carbonyl and the α-amino carbon. A fixed receptor model approach with a dispersion-corrected density functional, clearly discerned the effect of different substituents at both these positions using either a flexible or partially fixed ligand optimized in the presence of a fixed receptor model of the HDAC8 binding site. An electron donating substituent such as methyl at the C(α) in combination with NMe(2) substitution at the carbonyl position, similar to observed crystal structures, result in the optimal energetic profile for binding the zinc atom in the HDAC8 enzyme.