6SPT

High resolution crystal structure of N-terminal domain of PEX14 from Trypanosoma brucei in complex with the fist compound with sub-micromolar trypanocidal activity

Summary for 6SPT

• Entry DOI: 10.2210/pdb6spt/pdb
• Descriptor: Peroxin 14, 5-[(4-methoxynaphthalen-1-yl)methyl]-1-[2-[(2-methyl-1-oxidanyl-propan-2-yl)amino]ethyl]-~{N}-(naphthalen-1-ylmethyl)-6,7-dihydro-4~{H}-pyrazolo[4,3-c]pyridine-3-carboxamide, BETA-MERCAPTOETHANOL, ... (5 entities in total)
• Functional Keywords: pex5-pex14 protein protein inhibitor, hat, peroxisome, trypanosoma, signaling protein
• Biological source: Trypanosoma brucei brucei
• Total number of polymer chains: 1
• Total formula weight: 8851.03

Authors

Napolitano, V.,Dawidowski, M.,Kalel, V.C.,Fino, R.,Emmanouilidis, L.,Lenhart, D.,Ostertag, M.,Kaiser, M.,Kolonko, M.,Schilebs, W.,Maser, P.,Tetko, I.,Hadian, K.,Plettenburg, O.,Erdmann, R.,Sattler, M.,Popowicz, G.M.,Dubin, G. (deposition date: 2019-09-02, release date: 2020-01-01, Last modification date: 2020-02-05)

Primary citation

Dawidowski, M.,Kalel, V.C.,Napolitano, V.,Fino, R.,Schorpp, K.,Emmanouilidis, L.,Lenhart, D.,Ostertag, M.,Kaiser, M.,Kolonko, M.,Tippler, B.,Schliebs, W.,Dubin, G.,Maser, P.,Tetko, I.V.,Hadian, K.,Plettenburg, O.,Erdmann, R.,Sattler, M.,Popowicz, G.M.
Structure-Activity Relationship in Pyrazolo[4,3-c]pyridines, First Inhibitors of PEX14-PEX5 Protein-Protein Interaction with Trypanocidal Activity.
J.Med.Chem., 63:847-879, 2020

PubMed Abstract: protists are pathogens leading to a spectrum of devastating infectious diseases. The range of available chemotherapeutics against 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 , including the human pathogen and parasites.

PubMed: 31860309
DOI: 10.1021/acs.jmedchem.9b01876

Experimental method

X-RAY DIFFRACTION (1.2 Å)