ESR11: Fragment-based approaches to identify novel PPI inhibitors

Host: VU University Amsterdam, The Netherlands
Academic supervisors: Dr. Jacqueline van Muijlwijk and prof. dr. Iwan de Esch (VU University Amsterdam)
Researcher: Lorena Zara 

Download the full description of this project: ESR11: Fragment-based approaches to identify novel PPI inhibitors

Synopsis
FBLD technologies are continuously being improved to capture new opportunities. This project will interrogate emerging antimicrobial targets by fragment hit identification and fragment growing, linking and merging approaches.

Objectives
Design and synthesise compounds for antimicrobial protein targets, starting from existing hits of fragment library screening. 2. Perform ITC and SPR screening and develop ligand binding models. 3. Develop accurate ligand-­‐protein binding models using X-­‐ray, 15N-­‐NMR data and CADD data (in collaboration with ESR5).

Approach
In a joined effort with Zobio, VU University Amsterdam is exploring a couple of antimicrobial targets using FBLD approaches. In this project we will design and synthesize optimized hit fragments and drug-­‐like compounds. Computer-­‐aided drug design will be combined with the synthesis of series of compounds that interrogate the protein targets. Using the biochemical and biophysical screening data that will be generated (amongst others by ESR5), structure-­‐activity relationships, structure-­‐kinetics relationships and structure-­‐thermodynamics relationships will be explored and used to optimize the hit fragments.

Qualifications
Applicants must have a background in medicinal chemistry and have ample experience in computer-­‐aided drug design and the synthesis and characterisation of novel ligands. We are looking for an enthusiastic team player that is eager to collaborate with others.

Key publications
1. Edink et al. J.Am. Chem. Soc. 2011, 133, 5363-5371.
2. De Kloe  J. Med. Chem. 2010, 53, 7192-7201.

• 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
• 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