On the hunt for metalloenzyme inhibitors: Investigating the Presence of Metal-Chelating Compounds in Screening Libraries and Chemical Spaces

Metalloenzymes play vital roles in various biological processes, requiring the search for inhibitors to develop treatment option for diverse diseases. While screening compound libraries is a conventional approach, exploring virtual chemical spaces housing trillions of compounds has emerged as an alternative strategy. In this study, we investigated the suitability of selected screening libraries and chemical spaces for discovering inhibitors of metalloenzymes featuring common ions (Mg2+, Mn2+, and Zn2+). First, metal-chelating groups from ligands interacting with ions in the Protein Data Bank (PDB) were extracted. Subsequently, the prevalence of these groups in two focused screening libraries (Life Chemicals' chelator library, comprising 6,428 compounds, and Otava's chelator fragment library, with 1,784 fragments) as well as two chemical spaces (GalaXi, and REAL space, containing billions of virtual products) was investigated. In total, 1,223 metal-chelating groups were identified, with about a quarter of these groups found within the examined libraries and spaces. Our results indicate that these can serve as valuable starting points for drug discovery targeting metalloenzymes. Additionally, this study suggests ways to improve libraries and spaces for better success in finding potential inhibitors for metalloenzymes.