TY - JOUR

T1 - Computer-Aided Design and Synthesis of a New Class of PEX14 Inhibitors

T2 - Substituted 2,3,4,5-Tetrahydrobenzo[F][1,4]oxazepines as Potential New Trypanocidal Agents

AU - Fino, Roberto

AU - Lenhart, Dominik

AU - Kalel, Vishal C.

AU - Softley, Charlotte A.

AU - Napolitano, Valeria

AU - Byrne, Ryan

AU - Schliebs, Wolfgang

AU - Dawidowski, Maciej

AU - Erdmann, Ralf

AU - Sattler, Michael

AU - Schneider, Gisbert

AU - Plettenburg, Oliver

AU - Popowicz, Grzegorz M.

N1 - Funding Information: R.F., C.A.S., V.N., R.B., M.S., G.S., and G.P. would like to acknowledge the European Union’s Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under the Marie Skłodowska-Curie Grant Agreement No. 675555 and Accelerated Early staGe drug dIScovery (AEGIS) for the economic support. R.E., W.S., and V.C.K. were supported by the Deutsche Forschungsgemeinschaft grant FOR1905, FoRUM grants (F883–2016 and F913–2017) of the Ruhr-University Bochum, and Bundesministerium für Bildung and Forschung grant PEXMED. M.D. is grateful to the National Science Center Poland that provided funding through grant number UMO-2018/31/B/NZ7/02089. This work is also supported by the Helmholtz Association Initiative and Networking Funds under project number ZT-I-0003.

PY - 2021/10/25

Y1 - 2021/10/25

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85117182273&partnerID=8YFLogxK

U2 - 10.1021/acs.jcim.1c00472

DO - 10.1021/acs.jcim.1c00472

M3 - Article

AN - SCOPUS:85117182273

VL - 61

SP - 5256

EP - 5268

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

SN - 1549-9596

IS - 10

ER -