Mots-Clés

In silico design high throughput screening chemical libraries computational inhibition, docking ligand profiling

Description

Context
In the frame of project call named POC in labs 2024, the project entitled "Licence to kill" was selected to identify in silico and validate in vitro synergistic inhibitors to stop Multi Résistant infection to Staphylococcus Aureus (MRSA). The project is coordinated by Gwenaëlle André at MaIAGE (in silico part) and by Alexandra Gruss at Micalis (in vitro part). Staphylococcus aureus is a first cause of antibiotic resistance-related deaths. Finding new functional antibiotics is a challenge. Bacterial membranes contain untapped targets for antimicrobial discovery, whose unique features minimize cross-reactivity with their hosts. We identified targets of a pathway whose double-inactivation blocks MRSA growth. Starting with known drug-target, we aim to identify in silico inhibitors of the 2nd target, and test them in vitro. The optimal drug couples will be patented.

Assignment
The engineer will work alongside the members of the research team to study the capacity of small molecules to interact with the 2 nd target of the pathway, in its physiological form, collecting intensive ligand dockings, extracting pharmacophoric features, setting up molecular dynamics (MD) simulations data, building data frames for further development, etc. Expertise in high throughput screening will be essential for interpreting molecular data of the complexes and facilitating the development of a dedicated pipeline. The engineer will also be expected to stay aware of the latest methodologies in both high throughput screening and post-processing to enhance the quality and efficiency of the research outputs. The position will be supervised by Gwenaëlle André (Research Director) and Sylvain Marthey (Research engineer). Our team is part of StatInfOmics team with dozens of permanent researchers and several PhD and postdoc members. Our main goal is to predict structure, interaction, function and inhibition to further identify synthetic molecules of bacterial proteins selected upon their role in Antibio Resistance. The team has access to computational resources, including efficient GPUs and CPUs, from different cluster centers including Romeo (Reims), IFB, etc. The engineer will collaborate closely with two research teams, StatInfOmics of MaIAGE which is the host team and MicrobAdapt of MICALIS. Both teams are part of the INRAE Campus, located in the nice valley of Bièvres at Jouy-en-Josas. This recruitment will seal the collaboration, initiated here with the mutual objective to synergize our efforts against anti-bioresistance.

Main activities
1. Molecular analysis of the 3D structure of the target and characterization of the druggable pocket
2. Create a dataset of reference ligands by filtering Zinc20 chemical database to retain compounds fulfilling specific properties (HB donor/acceptor, aromatic ring, etc.)
3. Perform and manage highly intensive screening through molecular docking
4. Analysis of the best hits and identification of their pharmacophoric features
5. Implement the designed pipeline with the Snakemake workflow manager
6. Document procedures, results, and insights to support ongoing research efforts.

Skills
- Master or PhD degree in Computer Science, or Bioinformatics
- Proficiency in programming languages (Python) and good coding practices
- Expertise in molecular docking (Autodock4/ Autodock Vina)
- Expertise in Plip Protein-ligand interaction profiler or related programs
- Ability to work independently and also to work in a team
- Strong analytical and problem-solving skills.
- Oral and written English skills are a bonus