ESR5: Biophysics Based FBLD

Host: ZoBio BV, The Netherlands (PhD enrolment at VU University Amsterdam)
Industrial supervisor: Dr. Gregg Siegal (Zobio)
Researcher: Sébastien Keiffer

Download the full description of this project: ESR5: Biophysics Based FBLD

Synopsis
FBLD technologies are continuously being improved to capture new opportunities. This project will investigate emerging antimicrobial targets with state-­‐of-­‐the-­‐art biophysical screening technologies.

Objectives
Use NMR and SPR to screen a fragment library for validated hits against the target protein. 2. Develop NMR structural biology approaches to enable structure based drug design to elaborate hits to potent lead-­‐like molecules. 3. Collaborate with the medicinal chemistry group of Prof. Iwan de Esch to design, synthesize and test elaborated hits.

Approach
This project will seek to develop inhibitors of critical bacterial and/or viral enzymes. In order to do so we will first concentrate on expressing the target in E. coli in a form that is suitable for biophysical and structural biological work. The recombinant protein will be used to screen for ligands specific for the target using ZoBio’s proprietary, NMR-­‐based TINS technology and SPR. The structure of validated hits from this effort bound to the target will be elucidated using protein observed NMR methods. Collaboration with other Fragnet members will bring the possibility to use X-­‐ray crystallography as well. The structural information will be used to design compounds with better potency and ligand efficiency in collaboration with the medicinal chemistry group of Prof. Iwan de Esch. We expect to develop novel compounds that have biological activity in anti-­‐bacterial or anti-­‐viral assays.

Qualifications
A strong bachelors background in chemistry and physical chemistry is important. The successful applicant will have demonstrated some ability to recombinantly express and purify proteins. Any previous experience with NMR, either theoretical or practical, would be a help.

Key publications:
1. van Linden et al. Eur. J. Med. Chem. 2012, 47, 493-500.
2. Vanwetswinkel et al. Chem. Biol. 2005, 12, 207-216.
3. Shah et al. J. Med. Chem. 2012, 55, 23, 10786-10790.

Other projects

• 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
• 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
• ESR14: Targeting allosteric pockets with FBLD – Lena Münzker
• ESR15: Science, Business & Innovation in the pharmaceutical sciences – Angelo Kenneth Romasanta