Doctoral Candidate (PhD position) in Marie Sklodowska-Curie Horizon Europe DN Project: In Silico targeting of unstructured extracellular histones: En route to a new horizon of drug discovery to target disordered proteins (DC6)

PRAETORIAN

Would you like to be part of a network to collaboratively work to develop novel approaches in precision sepsis patient care providing new diagnostics and therapeutics? Would you like to start your career in a European training network of leading research universities, patient organisations and professionals from the industry to become a completely new type of actor in the field?

PRAETORIAN offers a top-level interdisciplinary research and educational training on preclinical and clinical science, business- and entrepreneurial aspects, intellectual properties and more, covering multiple aspects of the drug discovery and development process.

PRAETORIAN is an EU funded doctoral network coordinated by the Cardiovascular Research Institute Maastricht (CARIM), The Netherlands. PRAETORIAN brings together five university partners from across Europe to recruit a group of 10 of the best doctoral candidates. You will work together with senior researchers from across the network. You will be employed at one of the five academic institutions and enrolled in a local PhD programme, while at the same time being part of an integrated research team and research project at network level.

Objectives:

1. To apply specialistic state-of-the-art computational methods and develop novel computational approaches to identify peptides and small compounds to target unstructured N-terminal domains of histones. The identified inhibitors will be experimentally tested for their potential to reduce histones-mediated cytotoxicity.
2. To proof the concept that disordered proteins (e.g. histones) can be targeted by small compounds.
3. To develop new diagnostic tools (imaging probes) for sepsis by targeting extracellular histones.

Project description

In this project, DC6 will utilize various computational methods such as molecular docking, structure-based design, molecular dynamics (MD) simulations, and binding free energy (BFE) calculations to develop novel inhibitors (e.g. small compounds and peptides) to neutralize the cytotoxicity of extracellular histones. Furthermore, DC6 will examine the inhibitory activity of the developed compounds in different experiments such as in vitro and cell-based assay, direct binding measurement (i.e. Biacore Surface plasmon resonance (SPR) and/or nano ITC). At the host lab, DC6 will work closely with DC7 who will apply similar approaches to develop novel bioactive compound targeting the PAD2/4 enzyme. Within the consortium, DC7 will work collaboratively with DC2 and DC10 who will investigate biological activity and therapeutic benefits of the developed compounds (small compounds, peptides and diagnostic tools) in different experiments from in vitro to animal models. This project will enable DC6 to become proficient in both 'dry' and 'wet' labs and specialize in various computational and experimental techniques used in drug discovery campaigns.

Click here for more information on the network. criteria and application procedure.