jm9b01876_si_003.pdb (65.57 kB)
Structure–Activity Relationship in Pyrazolo[4,3‑c]pyridines, First Inhibitors of PEX14–PEX5 Protein–Protein Interaction with Trypanocidal Activity
dataset
posted on 2020-01-06, 13:34 authored by Maciej Dawidowski, Vishal C. Kalel, Valeria Napolitano, Roberto Fino, Kenji Schorpp, Leonidas Emmanouilidis, Dominik Lenhart, Michael Ostertag, Marcel Kaiser, Marta Kolonko, Bettina Tippler, Wolfgang Schliebs, Grzegorz Dubin, Pascal Mäser, Igor V. Tetko, Kamyar Hadian, Oliver Plettenburg, Ralf Erdmann, Michael Sattler, Grzegorz M. PopowiczTrypanosoma protists are pathogens
leading to a spectrum of devastating infectious diseases. The range
of available chemotherapeutics against Trypanosoma is limited, and the existing therapies are partially ineffective
and cause serious adverse effects. Formation of the PEX14–PEX5
complex is essential for protein import into the parasites’
glycosomes. This transport is critical for parasite metabolism and
failure leads to mislocalization of glycosomal enzymes, with fatal
consequences for the parasite. Hence, inhibiting the PEX14–PEX5
protein–protein interaction (PPI) is an attractive way to affect
multiple metabolic pathways. Herein, we have used structure-guided
computational screening and optimization to develop the first line
of compounds that inhibit PEX14–PEX5 PPI. The optimization
was driven by several X-ray structures, NMR binding data, and molecular
dynamics simulations. Importantly, the developed compounds show significant
cellular activity against Trypanosoma, including the human pathogen Trypanosoma brucei
gambiense and Trypanosoma cruzi parasites.