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Fragment-Based Approach to Targeting IMPDH from Mycobacterium tuberculosis

Speaker: Alex Latta, PhD Candidate, Department of Chemistry & Chemical Biology, IUPUI Location: 402 N Blackford St. Indianapolis, IN 46202 LD 010

Host: McLeish

The World Health Organization estimates that 1 in 3 individuals are infected with Mycobacterium tuberculosis. In 2015 this disease, known as Tuberculosis (TB), was ruled as the cause of death for 1.8 million people worldwide. Although infection rates and deaths associated with TB have been slowly declining in recent years, new drug resistant strains of Mtb are emerging. Thus, new treatment options need to be explored. One such option is designing compounds to target inosine 5’-monophosphate dehydrogenase (IMPDH). IMPDH is a key enzyme in the synthesis of guanine nucleotides, and is emerging as a potential target in antimicrobial drug discovery. In this work, the identification of new, potent IMPDH inhibitors by a fragment-based and structure-guided approach is described. A library of 960 fragments was screened for inhibitory activity towards IMPDH which revealed 18 hit compounds. The most active of these compounds were selected for further kinetic and X-ray crystallographic analyses producing a fragment bound X-ray crystal structure. Two phenylimidazole derivative fragment molecules were observed bound in the NAD+ binding site in an IMPDH-IMP-fragment complex. Fragment growing and fragment linking strategies were then employed that resulted in the discovery of five compounds with ~1000-fold increase in binding affinity. Finally, these compounds were tested for in vivo activity against Mtb.