UC San Diego

Fragment-based drug discovery (FBDD) is a powerful approach for identifying molecules that inhibit therapeutically relevant targets, focusing on the elaboration of fragment 'hits' into compounds with enhanced inhibition and desirable pharmaceutical attributes. A significant challenge in metalloenzyme inhibition within FBDD is the repeated use of the same metal-binding pharmacophores (MBPs), which limits the development of novel inhibitors. This thesis presents innovative strategies for exploring and expanding the fragment library, aimed at developing inhibitors for metalloenzymes and thus overcoming existing limitations. It also demonstrates how the enhanced fragment libraries have facilitated the identification of hit compounds targeting therapeutically relevant metalloenzymes. Metal-binding isosteres (MBIs) are introduced as a strategy to diversify fragment libraries for metalloenzyme inhibition. Isosteric replacement with 8-hydroxyquinoline was explored to enhance the potency and selectivity of drug-target interactions, as well as to broaden physicochemical properties of the fragments. Subsequently, this thesis includes an exploration of bioinorganic model complexes to study the structural and electronic characteristics of MBIs. MBIs of picolinic acid were investigated within different bioinorganic model systems, offering new insights into their properties. Furthermore, the strategic design of thioamide, thiourea, and thiocarbamate MBPs as potent warheads was showcased. Their potential in addressing the challenges of thiol-based MBPs, specifically against Zn(II)-dependent metalloenzymes, was demonstrated.I Lastly, the discovery of small molecule inhibitors against Cu-only Superoxide Dismutase (SOD5) demonstrates the identification and development of MBP/MBI warheads for a novel antifungal target. This significantly advances the quest for antifungal agents, underscoring the thesis's contribution to the development of metalloenzyme inhibitors through fragment-based strategies.