In Silico Screening Yields Novel Methylthioadenosine Nucleosidase Inhibitors and a Fast Track to New Anti-Parasitic Therapies
The parasites Giardia intestinalis and Entamoeba histolytica cause severe dysentery and are commonly spread through consumption of unclean drinking water. Metronidazole is the primary treatment of choice. Recently, metronidazole resistant parasite strains have emerged, underscoring the need to develop new antibiotics with unique mechanisms of action. The parasite enzyme methylthioadenosine nucleosidase (MTN) is a vital link in the recycling of methionine and purines required for growth and survival. Thus, MTN is a great anti-parasitic drug target. Unfortunately, traditional drug development requires nearly a decade of work and millions of dollars to implement. To accelerate the process, potential inhibitors identified by computer screens of drug databases, were tested against purified recombinant MTN enzymes from E. coli, G. intestinalis, E. histolytica, and human methylthioadenosine phosphorylase (MTAP) using a UV spectrophotometric assay. Several potent non-nucleoside MTN inhibitors were identified that showed nanomolar Ki values, while poorly binding to human MTAP. The ability to discriminate between these enzymes suggests that these drugs may be safe against human cells.
Schaefer, Jake and Hosek, Lauren, "In Silico Screening Yields Novel Methylthioadenosine Nucleosidase Inhibitors and a Fast Track to New Anti-Parasitic Therapies" (2015). College of Arts and Sciences Presentations. Paper 39.