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Fino, R. ; Lenhart, D. ; Kalel, V.C.* ; Softley, C. ; Napolitano, V. ; Byrne, R.* ; Schliebs, W.* ; Dawidowski, M.* ; Erdmann, R.* ; Sattler, M. ; Schneider, G.* ; Plettenburg, O. ; Popowicz, G.M.

Computer-aided design and synthesis of a new class of PEX14 inhibitors: substituted 2,3,4,5-tetrahydrobenzo[F][1,4]oxazepines as potential new trypanocidal agents.

J. Chem. Inf. Model. 61, 5256-5268 (2021)

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African and American trypanosomiases are estimated to affect several million people across the world, with effective treatments distinctly lacking. New, ideally oral, treatments with higher efficacy against these diseases are desperately needed. Peroxisomal import matrix (PEX) proteins represent a very interesting target for structure- and ligand-based drug design. The PEX5-PEX14 protein-protein interface in particular has been highlighted as a target, with inhibitors shown to disrupt essential cell processes in trypanosomes, leading to cell death. In this work, we present a drug development campaign that utilizes the synergy between structural biology, computer-aided drug design, and medicinal chemistry in the quest to discover and develop new potential compounds to treat trypanosomiasis by targeting the PEX14-PEX5 interaction. Using the structure of the known lead compounds discovered by Dawidowski et al. as the template for a chemically advanced template search (CATS) algorithm, we performed scaffold-hopping to obtain a new class of compounds with trypanocidal activity, based on 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepines chemistry. The initial compounds obtained were taken forward to a first round of hit-to-lead optimization by synthesis of derivatives, which show activities in the range of low- to high-digit micromolar IC₅₀ in the in vitro tests. The NMR measurements confirm binding to PEX14 in solution, while immunofluorescent microscopy indicates disruption of protein import into the glycosomes, indicating that the PEX14-PEX5 protein-protein interface was successfully disrupted. These studies result in development of a novel scaffold for future lead optimization, while ADME testing gives an indication of further areas of improvement in the path from lead molecules toward a new drug active against trypanosomes.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Matrix Protein Import; Prediction; Accuracy; Search; Models; Target

ISSN (print) / ISBN 0021-9576

e-ISSN 1520-5142

Journal Journal of Chemical Information and Modeling

Quellenangaben Volume: 61, Issue: 10, Pages: 5256-5268

Publisher American Chemical Society (ACS)

Publishing Place 1155 16th St, Nw, Washington, Dc 20036 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Structural Biology (STB)
Institute of Medicinal Chemistry (IMC)

Grants Helmholtz Association Initiative and Networking Funds
National Science Center Poland
Bundesministerium fur Bildung and Forschung grant PEXMED
FoRUM grants of the Ruhr-University Bochum
Deutsche Forschungsgemeinschaft
Accelerated Early staGe drug dIScovery (AEGIS)
European Union