Discovery of Novel Metalloenzyme Inhibitors Based on Property Characterization: Strategy and Application for HDAC1 Inhibitors

Metalloenzymes are ubiquitously present in the human body and are relevant to a variety of diseases. However, the development of metalloenzyme inhibitors is limited by low specificity and poor drug-likeness associated with metal-binding fragments (MBFs). A generalized drug discovery strategy was established, which is characterized by the property characterization of zinc-dependent metalloenzyme inhibitors (ZnMIs). Fifteen potential Zn²⁺-binding fragments (ZnBFs) were identified, and a customized pharmacophore feature was defined based on these ZnBFs. The customized feature was set as a required feature and applied to a search for novel inhibitors for histone deacetylase 1 (HDAC1). Ten potential HDAC1 inhibitors were recognized, and one of them (compound 9) was a known potent HDAC1 Inhibitor. The results demonstrated the effectiveness of our strategy to identify novel inhibitors for zinc-dependent metalloenzymes.

histone deacetylase; metal-binding fragments; metalloenzyme inhibitors; property characterization; virtual screening.