Former members

Supervisors

Dr. Nicolas RENAULT, Dr. Xavier DEZITTER

Research Title

Introduction to in silico drug design methods

Supervisors

Dr. Corentin BEDART

Research Title

In silico study of structure and protein-ligand interactions of FFA4 receptor for Drug Design

Supervisors

Dr. Amaury FARCE

Expertise

Supervisors

Dr. Nicolas RENAULT

Research Title

Introduction to in silico drug design methods

Supervisors

Dr. Corentin BEDART

Research Title

Contribution to chemical library management software L-g-Chimio

Supervisors

Dr. Nicolas RENAULT

Expertise

Research Title

Polluants environnementaux (phtalates et plastifiants alternatifs) et rupture prématurée des membranes fœtales

Research Title

Deciphering the mechanism of action of the P28GST in the treatment of autoimmune inflammatory disorders

Supervisors

Dr. Amaury FARCE, Pr. Monique CAPRON

Research Summary

The P28GST from Schistosoma haematobium, a parasite Glutathione S-Transferase, is a drug candidate in clinical evaluation for the treatment of inflammatory diseases, including inflammatory bowel diseases and Crohn's diseases. This protein combines two enzymatic activities, Glutathione S-Transferase (GST) and Prostaglandin D2 Synthase (PGDS), in addition to epitopic properties. If the use of P28GST in an inflammatory context orients the immune response towards an immunoregulatory and anti-inflammatory profile and confers a very important therapeutic potential in autoimmune inflammatory diseases, the mechanisms of action involved remain incompletely elucidated.This thesis contributes to the understanding of the mode of action of P28GST by studying its enzymatic activities at the atomic level using in silico approaches. The use of classical molecular dynamics allowed to study with accuracy the movements of the amino acids of the catalytic site, and their differential participation between the two activities. As classical techniques were not sufficient, metadynamics were performed to further investigate the participation of an essential tyrosine in the initiation of enzymatic activities, in particular via the determination of its free energy profile. Finally, the binding site of the specific ligand of the PGDS activity, the prostaglandin H2, was identified by molecular docking and classical molecular dynamics. These results allowed us to consider the search for specific inhibitors of PGDS activity, by directly targeting the identified binding site, by high throughput virtual screening and molecular docking techniques. Finally, the biological validation of the identified inhibitors has been initiated, with first results on GST activity and epitopic properties.This work required the development of numerous scripts in Python and R, allowing the processing and analysis of all the data generated. These different scripts led to the development of an analysis software and a visualization plugin, SINAPs (Structural Interaction Networks Analysis Protocols), to highlight the molecular interaction networks structuring proteins within molecular dynamics trajectories or crystallographic structures.

Research Title

In silico analysis of the anti-inflammatory mechanisms of shP28GST

Supervisors

Dr. Amaury FARCE

Research Title

Prediction of aromatase disruption potential

Research Title

Virtual screening of a library of privileged fragments: Training in 2D-based and 3D-based virtual screening methods

Supervisors

Dr. Nicolas RENAULT

Research Title

In silico screening of NOD1 ligands

Research Title

In Silico study of CD1d/Ag complex : molecular bases to modulate iNKT cells immune response

Supervisors

Pr. Philippe CHAVATTE

Research Summary

Development of new ligands able to switch invariant Natural Killer T (iNKT) cells toward an immunostimulant Th1 or an immunoregulative Th2 profile is a great challenge that can lead to new therapeutic opportunities in the treatment of various auto-Immune diseases or cancers. In this context, understanding the polarizing effect of iNKT ligands is of a major interest. We hypothesized that the intensity and nature of the biological response could depend on the stability of the CD1d-T Cell Receptor (TCR) interactions under the influence of the antigen which could modulate the shape of CD1d. Thus, our goal was to study the impact of iNKT ligands on the structure of the CD1d molecule and find clues to help design Th1/Th2 selective ligands.Using structure-Activity relationships, docking and molecular dynamic analyzed by a mix of classical and in house tools, we compared the structural behavior of the human and mouse CD1d molecule loaded with different ligands inducing Th1 or Th2 immune response profile. From the analysis of our molecular dynamics trajectories, it appears that there are noticeable differences in the behaviour of human and mouse CD1d molecules, mainly caracterized by changes at the inter-Helix distance and an increase ligand mobility for human systems.One major result is the identification of a specific conformational state of the ligand sugar group which could be correlated, in the present study, to the biological Th2 biased response. The different methods and combinations of ligand and protein descriptors used to analyze the dynamics of the binary complexes provide a structural basis for predicting the very different dynamical behaviors of ligands in CD1d and might aid in the future design of new iNKT modulators.

Research Title

In silico structural study of G proteins-coupled receptors applied to the virtual screening of melatoninergic, serotoniriergic and cannabinergic ligands

Supervisors

Pr. Philippe CHAVATTE

Research Summary

Identified as highly relevant therapeutical targets, the MT, and MT2 melatonin receptors, the5-HT2C serotonin and the CB2 cannabinoid receptors, which belong to the rhodopsin-like G proteincoupledreceptors (GPCRs) subfamily, have been studied by in silico approaches in order to identifycritical structural features for the binding, the selectivity and the pharmacological activity of theirligands. Gaining by sottie recent crystallographic data, various conformational states of these fourreceptors have been modeled according to the expected pharmacological profile. The comparativestudy of these various conformational states by molecular dynamics simulations has led to emphasizethe crucial rôle of the E2 extracellular loop and hélix 6 in the activation mechanisms of these GPCRs.On the basis of chemoinformatic methods, the virtual ligand screening targeting these threedimensionalmodels has promoted the characterization of a 5-HT2C receptor model able to bindspecifically inverse agonist ligands and the identification of pharmacological hits targeting the MTiand CB2 receptors.

Supervisors

Pr. Philippe CHAVATTE

Research Title

Study of cytochrome CYP5A1 mutations and molecular modeling