PLUS - Simulation des interactions des protéine-ligand dans le contexte du Fragment-Based Drug Design

 Fiche  technique du Projet

• Programme : Jeunes Chercheurs – Jeunes Chercheuses  - ANR 2011
• Coordinateur: Université Claude Bernard Lyon 1, Isabelle KRIMM
• Partenaires :
o Université Claude Bernard Lyon 1

• Coût Total: 717 644 €
• Contribution ANR : 171 444 €
• Durée : 2012 - 2015
• Projet Labellisé Lyon Biopôle



Context / Contexte

New methods including experimental data are required to allow a fast evaluation of the binding site and binding mode of the fragments once they have been detected as ligands in screening experiments. Here we propose to develop a software to filter the poses obtained from docking programs, using quantitatively the Chemical Shift Perturbations (CSP) observed in protein NMR spectra upon fragment addition. This project, which deals with fundamental research, will have a strong impact both in the field of Chemical Biology and Drug Design.

The coordinator of the proposal has introduced and developed the FBDD approach in the LSA Laboratory. A 250-fragment library was designed and NMR methods are currently used to (1) apply the FBDD techniques to design new active molecules in collaboration with chemists groups and (2) study the fragment-protein interactions in terms of affinity, specificity and binding properties (multiple-binding sites, multiple binding modes).


Objectives / objectifs

The main objectives of this proposal are the following:
(1) Assessment of the ring current effect as the major source of CSP for the study of weak fragment protein complexes;
(2) Assessment of the quantitative CSP as a tool to filter the docking poses.
(3) Investigation of the multiple binding sites and multiple binding modes of the fragments.

Program The scientific program is organized with the following tasks:
- Task 1: Coordination,
- Task 2: Production of protein samples
- Task 3: Programming of the Chemical Shift Perturbation Simulation
- Task 4: Identification of ligands by Ligand-Observed NMR experiments
- Task 5: Measurement of CSPobs through Protein-Observed NMR Experiments
- Task 6: Docking calculations
- Task 7: Simulation of CSPcalc
- Task 8: Comparison of observed and simulated CSP
- Task 9: Software Programming


Rôle de LIP

LIP a accompagné le projet dans sa phase de montage : définition des attendus du financeur, montage administratif et financier du projet, conseil à la rédaction.
LIP accompagne également ce projet dans son déploiement : recherche de partenaires, valorisation, transfert, captage de financements complémentaires...