ESR14: Targeting allosteric pockets with FBLD
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New inhibitors for Trypanosoma brucei farnesyl pyrophosphate synthase by fragment-based drug discovery
African sleeping sickness, caused by the parasite Trypanosoma brucei (T. brucei), is a neglected disease with an endemic occurrence in 36-sub-Saharan African countries As the current options for drug treatment have low efficacy and also strong side effects, new drugs with a better safety and efficacy profile are urgently needed. This project therefore took a fragment-based drug-discovery approach to identify new inhibitors for the T. brucei farnesyl pyrophosphate synthase (FPPS).
Nitrogen-containing bisphosphonates are the current treatment for bone diseases and have been shown to block the growth of the T. brucei parasites by inhibiting FPPS, an enzyme involved in sterol biosynthesis. However, due to their particular pharmacokinetic properties they are not well suited for non-bone indications. In previous efforts at Novartis, an allosteric pocket of human FPPS was identified by fragment-based drug discovery, allowing modulation of human FPPS by non-bisphosphonate inhibitors. As a similar pocket also exists in T. brucei FPPS, we drew on a fragment-based drug discovery approach to identify inhibitors of a new chemotype for T. brucei FPPS.
This work involved expressing and purifying T. brucei FPPS protein and applying it for an X-ray and NMR fragment screen. Fragments were screened by 1D-NMR and further validated and characterized in protein-observed 2D-NMR and the exact binding mode was determined in crystallization experiments. An X-ray fragment screen was performed in collaboration with the EMBL Grenoble using the automatic crystal harvesting pipeline. A 500 fragment library was screened and weak fragment binders were identified with the PanDDA (Pan-Dataset Density Analysis) software.
Fragment hits identified and characterized by NMR and X-ray techniques provided the starting points for medicinal chemistry, the overall goal being to optimize initial fragment hits into tool compounds with a high binding affinity that inhibit the FPPS enzyme function and parasitic growth.
• Jahnke, W., et al. (2010). “Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery.” Nat Chem Biol 6(9): 660-666.
• Marzinzik, A. L., et al. (2015). “Discovery of Novel Allosteric Non-Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthase by Integrated Lead Finding.” ChemMedChem 10(11): 1884-1891.
• Muenzker L., et al. Identification of an allosteric binding pocket on Trypanosoma brucei FPPS and implications for Human African Sleeping sickness, manuscript in preparation
• Muenzker L., et al. Allosteric and active site non-bisphosphonate binders identified by fragment-based discovery, manuscript in preparation Poster: • Muenzker L., Petrick J., Klebe G., Marzinzik A., Jahnke W., Targeting Trypanosoma brucei FPPS by fragment-based drug discovery, 9th International Conference on Structural Biology, 18th-20th September 2017, Zurich, Switzerland
• Muenzker L., Petrick J., Klebe G., Marzinzik A., Jahnke W., Fragment-based discovery of novel active and allosteric site binders of T. brucei farnesyl pyrophosphate synthase, 3rd Integrative Structural Biology School, 16th – 21st July 2018, Institut Pasteur, Paris, France Presentation:
• Muenzker L., Fragment-based discovery of novel active and allosteric site binders of T. brucei farnesyl pyrophosphate synthase, Fragment-based Lead Discovery Conference, 7th – 10th October 2018, San Diego, USA
- ESR1: 3D Fragments with small aliphatic rings – David Hamilton
- ESR2: Novel 3D fragments – Hanna Francesca Klein
- ESR3: Warhead Library of Covalent Fragment Binders – Aaron Keeley
- ESR4: Development of FBLD techniques for Intrinsically Disordered Proteins – Darius Vagrys
- ESR5: Biophysics Based FBLD – Sébastien Keiffer
- ESR6: FBLD experimental methods – Edward Fitzgerald
- ESR7: Understanding PDE binding kinetics – Pierre Boronat
- ESR8: Virtual Screening of Fragment Libraries of Covalent Binders – Andrea Scarpino
- ESR9: Fragment evolution platform – chemical navigation – Moira Rachman
- ESR10: Fragment evolution platform – molecular simulations – Maciej Majewski
- ESR11: Fragment-based approaches to identify novel PPI inhibitors – Lorena Zara
- ESR12: Covalent fragments to activate industrial enzymes – Eleni Makraki
- ESR13: Fragment-based assessment of new antibiotic target – Bas Lamoree
- ESR15: Science, Business & Innovation in the pharmaceutical sciences – Angelo Kenneth Romasanta
Please contact us at:
VU University Amsterdam
Marie Curie Actions
EU Horizon 2020