D3R Grand Challenge 2 · 2017. 3. 30. · Desaphy et al., Encoding protein-ligand interaction...
Transcript of D3R Grand Challenge 2 · 2017. 3. 30. · Desaphy et al., Encoding protein-ligand interaction...
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Docking Pose Selection by Interaction Pattern Similarity
D3R Grand Challenge 2
Dr. Didier RognanStructural Chemogenomics – Laboratory of Therapeutic InnovationFaculty of Pharmacy - University of Strasbourg - Francehttp://bioinfo-pharma.u-strasbg.fr
Dr. Priscila FigueiredoPost-doc , CAPES Biocomputational – University of Rio de Janeiro - Brazil
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OUTLINE
Structure selection
Protein & ligands preparation1
Docking and re-scoring protocol
Pose Prediction accuracy
Failures
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4What have we learned from the challenge?
Advantages of the method
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System setup
Templateselection
• 26 FXR x-ray structures (ligand-bound) available and extracted from the PDB;
Proteinpreparation
• Hydrogens added using PROTOSS v2.0 (Bietz et al. J. Cheminform. 2014, 6, 12);• Protonation of the active site residues verified;• Ligand and loosely-bound water ( < 2 intermolecular H-bonds) removed;
FXR ligands preparation
• 3D coordinates generated using CORINA (MOLECULAR NETWORKS GMBH);
• Protonation state assigned using FILTER (OPENEYE) and verified.
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1OSH 1OSV 1OT7(A) 1OT7(B) 3BEJ 4QE6
3DCT 3DCU 3FLI 3FXV 3GD2
3HC5 3HC6 3L1B 3OKH 3OKI
3OLF 3OMK 3OMM 3OOF 3OOK
3P88 3P89 3RUT 3RUU 3RVF
Docking protocol
FXR_1
FXR_102
…
102 FXR ligands
Surflex-Dock
102 x 26 x 20 = 53 040 poses
• Residue-based protomol• 6.5 Å around bound ligands
• pgeom option
• 20 poses/ligand
x 26 x-ray templates
Jain, J. Med. Chem., 2003, 46, 499-511.
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Scoring: Interaction pattern matching (GRIM)
Protein-Ligand Complex Interactions pseudoatoms (IPAs)
Graph-based alignment of IPAs
Alignment quantification by GRIMscore
GRIMscore = K + a*NLig + b*NCenter + c*NProt
+ d*SumCl –e*RMSD – g*DiffI
NLig: number of matched ligand-based IPAs
Ncent: number of matched centered IPAs
NProt: number of matched protein-based IPAs
SumCl:σ pair weights in clique
σ all possible pair weights
RMSD: root-mean square deviation of the matched clique
DiffI: absolute value of the difference in the number of IPAs between reference and query.3ert vs. 2r6y (GRIMScore = 0.804)
Desaphy et al. J. Chem. Inf. Model, 2013, 53, 623-633.
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GRIM Pairwise comparisons
(~53000 * 26)
Pose rescoring using GRIM
53 040 poses
26 FXR-ligand templates (PDB)
FINAL POSES
FXR-1-1
…
FXR_36-5
Surflex score > 2 (-logKd)
5 best GRIMscoresfor each ligand
1OSH
. . .
4QE6
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Pose prediction accuracy (35 ligands, FXR_1:FXR_36)
FXR_33 omitted
3.67 3.11 4.04 1.57
GRIM-1 GRIM-best Surflex-1 Best
Ave
rage
RM
SD(Å
)
No real docking problemAverage best pose: 1.57 Å
Real scoring problemGRIMscore > Surflex score
Highest GRIMscore Best of top5 GRIMscores Highest Surflex-Dock score Absolute Best rmsd7
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Pose prediction accuracy (35 ligands, FXR_1:FXR_36)
FXR_33 omitted
0
2
4
6
8
10
12
14FX
R_1
FXR
_2FX
R_3
FXR
_4FX
R_5
FXR
_6_
AA
FXR
_6_
AB
FXR
_7_A
AFX
R_7
_A
BFX
R_8
FXR
_9FX
R_1
0FX
R_1
1FX
R_1
2_A
AFX
R_1
2_A
BFX
R_1
3FX
R_1
4_A
AFX
R_1
4_A
BFX
R_1
5FX
R_1
6FX
R_1
7FX
R_1
8FX
R_1
9FX
R_2
0FX
R_2
1FX
R_2
2FX
R_2
3FX
R_2
4FX
R_2
5FX
R_2
6FX
R_2
7FX
R_2
8FX
R_2
9FX
R_3
0FX
R_3
1FX
R_3
2FX
R_3
4FX
R_3
5FX
R_3
6
RM
SD (
Å)
GRIM-1 GRIM-best Surflex-1 Best
Correctly posed (< 2 Å): n=20 (benzimidazoles)Incorrectly posed (> 2 Å): n=15
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0
2
4
6
8
10
0.7 0.8 0.9 1.0 1.1 1.2
RM
SD (
Å)
GRIMscore
Pose prediction accuracy (35 ligands, FXR_1:FXR_36)
FXR_33 omitted
0
2
4
6
8
10
0.2 0.4 0.6 0.8 1.0
RM
SD (
Å)
Chemical Similarity to Reference Ligand
GRIM-1 poses
Good pose when the reference ligand ischemically similar to the ligand to dock
Tc (MACCS keys)
Very high GRIMscores correspond to good posesNo strict correlation between GRIMscore and rmsd
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Pose prediction accuracy (35 ligands, FXR_1:FXR_36)
0
2
4
6
8
10
0 5 10 15
RM
SD (
Å)
Npolar
Npolar: number of matched polar interactions(H-bonds, ionic bonds)
Repeated failures when onlyapolar interactions are matched(High GRIMscore, Npolar = 0 or 1)
Good poses when the matched interaction pattern becomes more polar(High GRIMscore, Npolar ≥3)
FXR_33 omitted
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Reasons for failure
➢ Lack of polar interactions (high GRIMscore, Npol=0) FXR_4,8,10,12,15,16,18
➢ Low chemical similarity to any known co-crystallized FXR ligand (Tc <0.5): FXR_4,10,16,34
➢ Docking problem (rmsd >3Å): FXR_1,FXR_3
➢ Different binding mode: FXR_2
X-rayrefGRIMPredicted
rmsd: 5.15 ÅGRIMscore: 0.99Tc: 0.76
rmsd: 6.97ÅGRIMscore: 0.78Tc: 0.6
FXR_2
FXR_8
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0
2
4
6
8
10
12
RM
SD (
Å)
receiptID
Mean RMSD of Top Scoring Poses
GRIM rescoring vs other contributions
Incomplete predictions
GRIM
GRIM rescoring: 14th/46 complete predictions
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Ranking the ligands by affinity using HYDEStage-1
Sample slides available at: https://www.biosolveit.de/SeeSAR/science.html
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Results: ranking of the 102 FXR ligands
0.44
Best GRIMscore poseHYDE ranking
3rd/57 predictions
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What have we learned?
Pose predictionGRIM helps to rescue badly scored poses
GRIM rescoring relies on the availability of good templates (known binding modes)
Importance of polar interactions to generate a correct alignment
Structure-based scoringPose selection by GRIM and affinity ranking by HYDE is an efficient strategy
Protocol is fast enough (seconds) to be applicable at a higher throughput (VS hit list)
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Advantages of using GRIM
Can be coupled to any docking algorithm to post-process poses;
Take advantage of ligands with similar binding mode, not necessarily similar chemical
structures;
Can be applied in a target family-biased docking strategy
Module of the IChem toolkit (http://bioinfo-pharma.u-strasbg.fr/labwebsite/download.html)
Desaphy et al., Encoding protein-ligand interaction patterns in fingerprints and graphs. J. Chem. Inf. Model, (2013), 53:623-637
Slynko et al., Docking pose selection by interaction pattern graph similarity: application to the D3R grand challenge 2015. J Comput
Aided Mol Des (2016), 30:669-683 16
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Acknowledgments
Dr. Didier Rognan
Contact: [email protected]
Guillaume Bret Dr. Franck da Silva
[email protected]. Priscila Figueiredo