UC San Diego

The use of fragment-based lead discovery (FBLD) for the design and development of metalloenzyme inhibitors is examined. This thesis will first discuss the method of FBLD and compare it to more traditional drug discovery approaches, such as high-throughput screening (HTS). After establishing the concepts behind FBLD, the applications of utilizing a FBLD approach towards the development of inhibitors for select metalloenzymes is discussed. A study into the use of a chelator fragment library (CFL) to identify new metal-binding groups (MBG) for metalloprotein inhibitors is discussed. The results of screening this library against a number of metalloenzymes identified important trends between classes of chelators in addition to the identification of numerous metalloenzyme specific MBGs. Furthermore this study provides evidence that the CFL can be used as useful tool in metalloenzyme inhibitor design. A second probes the types of key interactions a metal-binding inhibitor must posses to effectively inhibit the dinuclear metalloenzyme HIV-1 integrase (HIV-1 IN). A small library of compounds varying only in composition of their MBG was prepared. The activity of this series of compounds was also compared to a similar HIV-1 IN FDA-approved drug. Screening this library of compounds led to the identification of a potentially unique and more potent scaffold (hydroxypyrone -based compounds) for HIV-1 IN inhibitors. Additionally, a small sublibrary of compounds was developed to explore the effects of manipulating the pKa of the chelator. The results of the systematic examination of the role the MBG contributes to HIV-1 IN inhibition are discussed. Lastly, the discovery of two novel metal-binding scaffolds for the development Pseudomonas aeruginosa elastase (LasB) inhibitors is discussed. Further use of the above mentioned CFL, helped to identify the first nonpeptidic small molecule inhibitors of LasB. These compounds, in addition to displaying selective antagonism for LasB against a panel of similar metalloenzymes, also confirmed the role the enzyme plays in the swarming behavior of this organism