docking@grid validation

1/18L. Brillet (CEA) – Docking@Grid ANR meeting – META’08 Hammamet

Docking@Grid validationDocking@Grid validation

Docking@Grid ANR meeting - 28/10/2008

• CEA Grenoble - DSV/iRTSV/CMBA (C. Barette, L. Lafanechère) et LTS (R. Prudent, C. Cochet)

• Laboratoire d’infochimie, ULP, Strasbourg (S. Conilleau , D. Horvath)

• LIFL, Lille (team of E.-G. Talbi)

L. Brillet, S. Roy (CEA Grenoble - DSV/iRTSV/CMBA)


Introduction

folding

redocking of PDB complexes

comparison with classical docking programs

activity prediction

DOCKING@GRID EVALUATIONDOCKING@GRID EVALUATION

1. Preparation of the PDB complexes

2. Evaluation with the protein kinase CK2 – comparison with Gold


ThrombinCK2 HIV-RT

reference coordinates for ligands superimposition of the complexes’ structures

preparation of the target H, charges, atomic types, file format, active site

preparation of the ligands corrections, H, charges, atomic types, file format

PREPARATION OF THE COMPLEXESPREPARATION OF THE COMPLEXES

3 families of PDB complexes redocking :

3BQC.pdb (human)23 ligands (human + maize)

1RT1.pdb11 ligands

1XM1.pdb10 ligands

Tools : Chimera, MOE, VegaZZ, ChemAxon


Evaluation with the protein kinase CK2

ATP or GTPProtein – substrate

phosphate

+ 300 substrates

CK2 abnormal expression: inflammation (viral) infection cancer

PROTEIN KINASE CK2PROTEIN KINASE CK2


in vitro activity in vivo activity selectivity SAR

DatabaseJChemBase (ChemAxon)

CK2 BIOLOGICAL DATACK2 BIOLOGICAL DATA

CEA Grenoble, DSV/iRTSV/LTS: R. Prudent, C. Cochet• Expanding the chemical diversity of CK2 inhibitors, Prudent et al., 2008, Mol. Cell.

Biochem.• Salicylaldehyde derivatives as new protein kinase CK2 inhibitors, Prudent et al., 2008, Bioch. Biophys. Acta

Evaluation with the protein kinase CK2

CEA Grenoble, DSV/iRTSV/CMBA: C. Barette, L. Lafanechère

HTS screening: ~ 12 000 compounds

post HTS studies: 5 groups of actives / inactives structural analogues (~ 100 compounds)


EVALUATION WITH CK2 – COMPARISON DOCKING@GRID - GOLD


Docking@Grid Gold (CCDC)

• co-cristallised ligands • set of analogues (known activity)• CMBA library (CEA): 35000 comp.

• co-cristallised ligands • others ?

docking docking

results resultsComparison ?

1 protein conformation

Hits selection in vitro tests


Gold Glide FlexX

PRELIMINARY STUDIESPRELIMINARY STUDIESComparison Docking@Grid - Gold

Revue of the litterature (docking, evaluation of the docking programs)

Training in D. Rognan’s laboratory (Strasbourg)

Choice of a docking program


1. Bibliography2. Preparation of the target3. Preparation of the library4. Design of the screening parameters 5. Screening of the library6. Post-processing / results analysis

VIRTUAL SCREENING ON CK2 WITH GOLD

VIRTUAL SCREENING ON CK2 WITH GOLD

Developed strategy:

Comparison Docking@Grid - Gold


33 publications 25 cristallised inhibitors-CK2 complexes (PDB)

- structure

- flexibility

- water molecules ?

- binding modes / interactions

BIBLIOGRAPHYBIBLIOGRAPHYComparison Docking@Grid - Gold

information about the active site:


emodin, 3BQC.pdb

Lys68

green = hydrophobicpink = polar


PREPARATION OF THE TARGETPREPARATION OF THE TARGET


Preparation

Choice of the

conformation


Unique ID

Protonation pH 7.4

Tautomers

Standardisation

2D 3D

PREPARATION OF THE LIBRARYPREPARATION OF THE LIBRARY

xx

xx

x


automated procedure:


DESIGN OF THE SCREENING PARAMETERS


1 - Docking of PDB complexes

check the pose (RMSD < 2A ?)


Docking protocole variations with Gold :

- water molecule n°2

- flexibility of the lateral chains

- number of genetic operations for each genetic algorithm run

- number of genetic algorithm runs per ligand

failures : no flexibility of the hinge region

good success rate


2 - Docking of a small set of actives / inactives

check the enrichment in actives

actives

inactives

% of actives

% of compounds ranked by score

100%

100%

random

enrichment





POST-PROCESSING / RANKING OF THE MOLECULES

POST-PROCESSING / RANKING OF THE MOLECULES

Strategies:

based on interaction fingerprints

+ diversity analysis


based on a consensus of scoring

functions

Optimizing Fragment and Scaffold Docking by Use of Molecular Interaction Fingerprints, G. Marcou & D. Rognan, 2007, J. Chem. Inf. Model.




Docking@Grid Gold (CCDC)

• co-cristallised ligands • set of analogues (known activity)• CMBA library (CEA): 35000 comp.

• co-cristallised ligands • others ?

docking docking

results resultsComparison ?

1 protein conformation

Hits selection in vitro tests


CEA: CMBA (C. Barette, L. Lafanechère), LTS (R. Prudent, C. Cochet, V. Moucadel),

Laboratoire d’Infochimie (ULP, Strasbourg): S. Conilleau, D. Horvath, G. Marcou

Bioinformatique du Médicament, Laboratoire de Pharmacochimie et de la Communication Cellulaire (ULP, Illkirch): D. Rognan and his team

CEA: GIPSE (C. Charavay, V. Dorffer, J.-P. Eynar), IBS (A. Thomas)

M. Lopez-Ramos (Institut Curie, Paris), J.-N. Denis (UJF), D. Giganti (Institut Pasteur, Paris)

Laboratoire d’Informatique Fondamentale de Lille: team of E.-G. Talbi

Conclusion

THANKSTHANKS


Docking@Grid validationDocking@Grid validation

Docking@Grid ANR meeting - 28/10/2008

• CEA Grenoble - DSV/iRTSV/CMBA (C. Barette, L. Lafanechère) et LTS (R. Prudent, C. Cochet)

• Laboratoire d’infochimie, ULP, Strasbourg (D. Horvath, S. Conilleau)

• LIFL, Lille (team of E.-G. Talbi)

L. Brillet, S. Roy (CEA Grenoble - DSV/iRTSV/CMBA)

docking@grid validation

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