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Host: University of Barcelona, Spain
Academic supervisor: Prof. Xavier Barril (University of Barcelona)
Researcher: Maciej Majewski

Download the full description of this project: ESR10: Fragment evolution platform – molecular simulations

For efficient hit optimisation, a thorough understanding of fragment-­‐protein binding is necessary. Computer‐aided drug design (CADD) approaches are able to generate accurate molecular models that integrate available structural data with biochemical and biophysical screening data. In this project, a computational platform will be established that will help to study the binding kinetics of fragment‐protein and ligand‐protein binding.

1.Development of fast simulation-­‐based methods for fragment screening and evolution.
2. Comparison of unbiased (association) and biased (dissociation) MD simulations for binding mode prediction and virtual fragment screening.
3. Integration of simulation-­‐based methods within the fragment evolution platform.
4. Prospective application of simulation-­‐based methods. 

The ESR will initially apply computational methods developed in the group (MDmix, Dynamic Undocking) to existing projects, andESR10 then proceed to implement advanced sampling molecular dynamics methods that extend the applicability of our current tools. The specific problems of fragment binding mode identification, virtual fragment screening and fragment evolution will be examined with several alternative approaches that will be systematically compared. Optimized protocols will be developed for specific problems and integrated within a fragment evolution platform that will be developed in parallel. The methods will be evaluated prospectively in collaboration with other ESRs.

Required diploma: MSc Computational Chemistry, Bioinformatics or similar degree and a background in chemistry, physics, pharmaceutical sciences or molecular life sciences. Required expertise: Experience in molecular simulations of biomolecular systems and a solid knowledge of statistical thermodynamics and biophysical methods. Recommended expertise: structural biology, molecular biology or synthetic chemistry would be an advantage. Experience with NMR, ITC, SPR would be highly valued. An interest in computer-­‐aided drug design and strong interpersonal skills are essential to establish fruitful collaborations within the consortium.

Key publications
1. Alvarez-Garcia et al. J. Med. Chem. 2014, 57, 8530–8539.
2. Alvarez-Garcia et al. J. Chem. Theory Comput. 2014, 10, 2608–2614.
3. Schmidtke et al. J. Am. Chem. Soc. 2011, 133, 18903-18910.
4. Seco et al. J. Med. Chem. 2009, 52, 2363-2371.

Contact details

Please contact us at:

FRAGNET Coordinator
VU University Amsterdam
The Netherlands

Funded by

marie curie actions   Marie Curie Actions



EU Horizon 2020



european union logo   European Union