7QRC

X-ray structure of Trypanosoma cruzi PEX14 in complex with a PEX5-PEX14 PPI inhibitor

Summary for 7QRC

• Entry DOI: 10.2210/pdb7qrc/pdb
• Descriptor: Peroxin-14, GLYCEROL, ~{N}-(5-ethyl-6-oxidanylidene-benzo[b][1,4]benzothiazepin-2-yl)-2-(4-fluorophenyl)ethanamide, ... (4 entities in total)
• Functional Keywords: structure-based drug design, inhibitor, trypanosomiasis, complex, pex5-pex14 ppi, signaling protein
• Biological source: Trypanosoma cruzi
• Total number of polymer chains: 2
• Total formula weight: 15946.35

Authors

Napolitano, V.,Popowicz, G.M.,Dawidowski, M.,Dubin, G. (deposition date: 2022-01-10, release date: 2022-11-23, Last modification date: 2024-01-31)

Primary citation

Napolitano, V.,Mroz, P.,Marciniak, M.,Kalel, V.C.,Softley, C.A.,Janna Olmos, J.D.,Tippler, B.G.,Schorpp, K.,Rioton, S.,Frohlich, T.,Plettenburg, O.,Hadian, K.,Erdmann, R.,Sattler, M.,Popowicz, G.M.,Dawidowski, M.,Dubin, G.
Structure-based design, synthesis and evaluation of a novel family of PEX5-PEX14 interaction inhibitors against Trypanosoma.
Eur.J.Med.Chem., 243:114778-114778, 2022

PubMed Abstract: Trypanosomiases are neglected tropical diseases caused by Trypanosoma (sub)species. Available treatments are limited and have considerable adverse effects and questionable efficacy in the chronic stage of the disease, urgently calling for the identification of new targets and drug candidates. Recently, we have shown that impairment of glycosomal protein import by the inhibition of the PEX5-PEX14 protein-protein interaction (PPI) is lethal to Trypanosoma. Here, we report the development of a novel dibenzo[b,f][1,4]oxazepin-11(10H)-one scaffold for small molecule inhibitors of PEX5-PEX14 PPI. The initial hit was identified by a high throughput screening (HTS) of a library of compounds. A bioisosteric replacement approach allowed to replace the metabolically unstable sulphur atom from the initial dibenzo[b,f][1,4]thiazepin-11(10H)-one HTS hit with oxygen. A crystal structure of the hit compound bound to PEX14 surface facilitated the rational design of the compound series accessible by a straightforward chemistry for the initial structure-activity relationship (SAR) analysis. This guided the design of compounds with trypanocidal activity in cell-based assays providing a promising starting point for the development of new drug candidates to tackle trypanosomiases.

PubMed: 36194937
DOI: 10.1016/j.ejmech.2022.114778

Experimental method

X-RAY DIFFRACTION (2.18 Å)