The pathogenic microorganism Trypanosoma cruzi is the causative agent of Chagas disease, one of the big health challenges of the American continent. Successful efforts were made during the last decades to control the transmission of the disease, but there is still no treatment for the 10 million adults in the chronic phase of the disease. In T. cruzi as well as in other pathogens the flavoenzyme UDP-Galactopyranose Mutase (UGM) catalyzes the conversion of UDP-galactopyranose to UDP-galactofuranose, a precursor of the cell surface compound �-Galactofuranose involved in the virulence of the pathogens. The fact that UGM is not present in humans makes inhibition of this enzyme a good approach in the design of new Chagas therapeutics. Unfortunately, since the active site of UGM is extremely polar, the few known competitive inhibitors have poor pharmacokinetic profiles, so alternative inhibition mechanisms are needed. Along these lines, it is thought that UGM controls substrate uptake by opening or closing a large channel. By performing a series of computer simulations of UGM, we found new druggable hot-spots as well as allosteric pathways involved in the opening of the tunnel that will be tested as potential therapeutic drugs for the chronic phase of Chagas disease.

Allosteric pathways and dynamics of UDP-galactopyranose mutase: Implications on drug design

245th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.