Virtual screening and inhibitor design against the mitosomal ADP/ATP carrier of Entamoeba histolytica

The human parasite Entamoeba histolytica is estimated to infect 50 million people world-wide and cause more than 150,000 deaths per year. The most common manifestation is amoebic dysentery, where the lining of the intestine is infected, but it can also invade and cause abscesses in lungs, liver and brain. The aim of this project is to carry out virtual screening to select drugs against the ADP/ATP carrier of Entamoeba that is involved in the import of ATP into the mitosome, a rudimentary mitochondrion. The mitosomal ADP/ATP carrier, which belongs to the mitochondrial carrier family, is phylogenetically and functionally unrelated to human ADP/ATP carriers and has been shown to be crucial for the growth and development of the parasite. High-throughput assays have been developed to screen for inhibitors of the carrier experimentally.

This PhD project will focus on the selection of compounds on the basis of cheminformatic analysis by using structure-based screening and molecular dynamics. Ligand-based screening will be run on the collections of all purchasable compounds to find molecules with similar chemical properties as the hit compounds. Molecular dynamics simulations with a comparative structural model of the ADP/ATP carrier will be carried out on the top hits to establish their potential mode of binding. The top compounds will be tested experimentally in inhibitor/IC50 assays to establish their efficacy. These results will provide information to find other related compounds with better binding properties and to improve the inhibitor-binding model in an iterative process.