ESR3: Warhead Library of Covalent Fragment Binders

Host: RCNS, Hungary (PhD enrolment at Budapest University of Technology and Economics)
Academic supervisor: Prof. dr. György M. Keserű (RCNS)
Researcher: Aaron Keeley

Download the full description of this project: ESR3: Warhead Library of Covalent Fragment Binders

Synopsis
The starting points of FBLD studies are highly curated collections of small, chemically diverse and highly soluble fragments. To increase the diversity of the available fragment libraries, ESR3 will design and synthesise a reactive ‘warhead’ library and establish techniques for screening covalent binders against several FragNet protein targets, including kinases.

Objectives
Designing and creating a compound library of fragment sized molecules with reactive warheads: “warhead library”. 2. Establishing techniques for efficient detection of covalent binders in a screening setup. 3. Screening of “warhead” library and virtual hits identified by ESR9 against various protein targets, e.g., Janus kinases. 4. Extending covalent binders into lead-­‐like compounds.

Approach
By using synthetic organic chemistry, computational chemistry and (structure-­‐based) drug design, a general fragment library for screening of covalent ligands will be created. The identification of covalent inhibitors for therapeutically relevant proteins, including Janus kinases, will be explored.

Qualifications
Preparative organic chemistry or theoretical organic chemistry or chemical biology knowledge and lab experience, analytical or bioanalytical background will be beneficial.

Key publications
1. Jöst et al. J. Med. Chem. 2014, 57, 7590-7599
2. Mark et al. J. Med. Chem. 2014, 57, 10072-10079
3. Baskin et al. PLoS ONE 2014, 9(8), e105568.

Other projects:

• ESR1: 3D Fragments with small aliphatic rings – David Hamilton
• ESR2: Novel 3D fragments – Hanna Francesca Klein
• 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
• ESR14: Targeting allosteric pockets with FBLD – Lena Münzker
• ESR15: Science, Business & Innovation in the pharmaceutical sciences – Angelo Kenneth Romasanta