UC San Diego

Metalloproteins are essential to a wide range of biological functions including nucleic acid modification, protein degradation, and many others. Metalloproteins that utilize a metal ion to facilitate catalysis are known as metalloenzymes. Due to their role in the proliferation of many diseases, ranging from diabetes, cancer, anxiety, and pathogenic infections, there has been an increased awareness and effort to target metalloenzymes for therapeutic intervention. This dissertation will focus on the utilization of a metal-binding pharmacophore library for the fragment-based drug discovery of novel New Delhi Metallo-β-lactamase-1 (NDM-1) inhibitors. NDM-1 is a metalloenzyme that hydrolyzes β-lactam containing antibiotics and contributes to the heightened threat of antibiotic resistance. NDM-1 Inhibitor development presented in this dissertation will focus on the conversion of traditional metal chelating fragments to compounds which form stable protein:inhibitor ternary complexes. Chapter 1 describes the current landscape of metalloenzyme inhibitors and relevant background information of NDM-1. Chapter 2 details the discovery of dipicolinic acid (DPA) as a lead fragment and the hit-to-lead development of DPA derivatives as inhibitors for NDM-1. The development of DPA isosteres and investigation in the relationship of observed inhibition value versus mechanism of action is presented in Chapter 3. The investigation of an alternative MBP, iminodiacetic acid (IDA), into a second class of novel NDM-1 inhibitors is described in Chapter 4. Chapter 5 includes a description of alternative synthesized libraries and perspective on the future of NDM inhibitor development. Together these chapters demonstrate the utility of fragment-based drug discovery and metal-binding pharmacophores for the development of novel and potent NDM-1 inhibitors.