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
posted on 2021-10-01, 23:44authored byRoberto Fino, Dominik Lenhart, Vishal C. Kalel, Charlotte A. Softley, Valeria Napolitano, Ryan Byrne, Wolfgang Schliebs, Maciej Dawidowski, Ralf Erdmann, Michael Sattler, Gisbert Schneider, Oliver Plettenburg, Grzegorz M. Popowicz
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.