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FRAGNET

Fragnet


Host: VU University Amsterdam, The Netherlands
Academic supervisors: Dr. Chris de Graaf and prof. dr. Iwan de Esch (VU University Amsterdam)
Researcher: Pierre Boronat

 

Download the full description of this project: ESR7: Understanding PDE binding kinetics


Synopsis
This project will investigate of binding kinetic while growing hit fragments, building on interesting data that has already been generated for Trypanosoma brucei Tbr-PDE ligands. The project will combine design, synthesis and molecular dynamics studies to unravel the molecular features of structure-kinetics relationships.

Objectives
1. Use SPR biosensors to measure the differences in binding kinetics of ligands for human hPDE4 and parasite TbrPDE proteins.
2. Perform Random Acceleration Molecular Dynamics (RAMD) studies to determine ligand access and egress mechanisms and factors determining the kinetics of ligand binding to PDEs.
3. Guide fragment hit growing to develop optimised compounds with well-­‐defined kinetic selectivity profiles.


Approach
Trypanosoma brucei (Tbr) is the causative parasite of human African trypanosomiasis (HAT), also known asESR8African sleeping sickness, a disease that has been grossly neglected as it is only a problem in the poorest areas of Africa. Tbr-­‐PDE enzymes are validated drug targets to treat this illness. These Fragnet studies will lead to a better understanding of kinetic binding properties of Tbr-­‐ PDE ligands. This molecular understanding can be used to achieve kinetic selectivity and thereby create safe and efficient drugs for this neglected disease.

Qualifications
AApplicants must have a background in molecular modelling (including molecular dynamics studies). Experience with organic synthesis or SPR biosensor instruments would be an advantage. The project can be fine-­‐tuned according to the background and interests of the successful candidate.

Key publications
1. Jansen et al. J. Med. Chem. 2013, 56, 2087-2096.
2. Orrling et al. Discov Today. 2012, 55, 8745-8756.

Other projects

Contact details

Please contact us at:
info@fragnet.eu

FRAGNET Coordinator
VU University Amsterdam
The Netherlands



Funded by

marie curie actions   Marie Curie Actions

 

 

unnamed   
EU Horizon 2020

 

 

european union logo   European Union