Screenscore - OpenEye Scientific Software
Screenscore - OpenEye Scientific Software
Screenscore - OpenEye Scientific Software
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Docking by Committee<br />
Mark McGann<br />
<strong>OpenEye</strong> <strong>Scientific</strong> <strong>Software</strong><br />
www.eyesopen.com
Exhaustive Docking<br />
• Rigid Docking<br />
• Systematic Search<br />
• Negative Image Filter<br />
• Grid based scoring<br />
• Shapegauss<br />
• PLP<br />
• Chemgauss<br />
• Chemgauss2<br />
• ~70ms/conformer<br />
Docking Process<br />
• Start with conformationally expanded ligand<br />
Optimization<br />
• Systematic (~20ms/pose)<br />
• Shapegauss<br />
• PLP<br />
• Chemgauss<br />
• Chemgauss2<br />
• Chemscore<br />
• <strong>Screenscore</strong><br />
• Full coordinate (~5sec/pose)<br />
• MMFF<br />
Scoring<br />
• Shapegauss<br />
• PLP<br />
• Chemgauss<br />
• Chemgauss2<br />
• Chemscore<br />
• <strong>Screenscore</strong><br />
• Zapbind (~1-5sec/pose)<br />
* Timings are on 1Ghz Pentium III
Shape /<br />
Lipophilic<br />
Donors /<br />
Acceptors<br />
Shapegauss PLP Chemgauss Chemscore <strong>Screenscore</strong> Zapbind<br />
YES YES YES YES YES YES<br />
NO YES YES YES YES NO<br />
Metal NO YES YES YES YES NO<br />
Aromatic NO NO YES NO YES NO<br />
Rotatable<br />
Bonds<br />
Scoring Function Components<br />
NO NO NO YES YES NO<br />
Electrostatics NO NO NO NO NO YES<br />
Speed<br />
Fast Medium Slow
Exhaustive<br />
Docking<br />
Fred 1.2 Docking Process<br />
Optimization Scoring<br />
Shapegauss Shapegauss<br />
Shapegauss<br />
Shapegauss<br />
PLP<br />
Chemscore<br />
<strong>Screenscore</strong><br />
PLP<br />
Chemscore<br />
<strong>Screenscore</strong><br />
* Dashed lines represents that only one path is taken<br />
PLP<br />
Chemscore<br />
<strong>Screenscore</strong><br />
> 10 5 Poses 10-100 Poses 1-10 Poses
Fred 2.0 Docking Process<br />
Exhaustive Docking Optimization Scoring<br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
MMFF<br />
Chemscore<br />
<strong>Screenscore</strong><br />
* Dashed lines represents that only one path is taken<br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
Zapbind<br />
Chemscore<br />
<strong>Screenscore</strong><br />
> 10 5 Poses 10-100 Poses 1-10 Poses
Gold Dataset<br />
• 224 Initial complexes<br />
• Remove<br />
– Covalent binders<br />
– Questionable chemistries<br />
• 175 Final Complexes<br />
PROTEINS: Structure, Function and Genetics 49:457 – 471 (202)
Best Omega Conformer
Exhaustive Docking<br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
Chemgauss2<br />
> 10 5 Poses<br />
Docking Process<br />
100 Poses<br />
* Dashed lines represents that only one path is taken
Exhaustive Search<br />
Best pose in Top 100 less than RMS x
Exhaustive Search<br />
Best pose in Top 100 less than RMS x<br />
Rms < 1.0 rms
Docking Process<br />
Exhaustive Docking Optimization<br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
Chemgauss2<br />
> 10 5 Poses<br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
Chemgauss2<br />
Chemscore<br />
<strong>Screenscore</strong><br />
* Dashed lines represents that only one path is taken<br />
Shapegauss<br />
PLP<br />
Scoring<br />
Chemgauss<br />
Chemgauss2<br />
Chemscore<br />
<strong>Screenscore</strong><br />
100 Poses 1 Pose
Optimization of exhaustive top 100<br />
Top ranked pose less than RMS x<br />
RMS
Optimization of exhaustive top 100<br />
Top ranked pose less than RMS x
Docking Process<br />
Exhaustive Docking Optimization Scoring<br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
Chemgauss2<br />
> 10 5 Poses<br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
Chemgauss2<br />
Chemscore<br />
<strong>Screenscore</strong><br />
* Dashed lines represents that only one path is taken<br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
Chemgauss2<br />
Chemscore<br />
<strong>Screenscore</strong><br />
100 Poses 1 Pose
Consensus Docking Process<br />
Exhaustive Docking Optimization Consensus<br />
Structure<br />
Scoring<br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
Chemgauss2<br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
Chemgauss2<br />
Chemscore<br />
<strong>Screenscore</strong><br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
Chemgauss2<br />
Chemscore<br />
<strong>Screenscore</strong><br />
* Dashed lines represents that only one path is taken<br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
Chemgauss2<br />
Chemscore<br />
<strong>Screenscore</strong><br />
> 10 100 Poses 1 Pose<br />
5 Poses 100 Poses
A<br />
B<br />
C<br />
D<br />
E<br />
F<br />
G<br />
Consensus Structure<br />
Comparing Pose vs. Pose not Ligand vs. Ligand<br />
Optimized<br />
conformer list<br />
Order poses by<br />
scoring functions<br />
A<br />
D<br />
F<br />
C<br />
B<br />
G<br />
E<br />
B<br />
E<br />
C<br />
D<br />
F<br />
G<br />
A<br />
G<br />
F<br />
E<br />
A<br />
D<br />
C<br />
B<br />
Create consensus<br />
list by rank<br />
F10<br />
D11<br />
A12<br />
B12<br />
E12<br />
C13<br />
G13<br />
Select top<br />
pose<br />
F10<br />
*Cost in CPU time for Consensus structure is ~1ms/pose
Consensus ranking of optimized poses<br />
Top ranked pose less than RMS x
Consensus ranking of optimized poses<br />
Top ranked pose less than RMS x<br />
Optimization Function RMS < 1 RMS < 1.5 RMS < 2.0<br />
Shapegauss 25% 45% 56%<br />
PLP 34% 54% 67%<br />
Chemgauss 29% 49% 60%<br />
Chemgauss2 30% 50% 60%<br />
Chemscore 33% 54% 66%<br />
<strong>Screenscore</strong> 35% 52% 63%<br />
Gold (224 complexes) 50% 65% 72%<br />
Docking time : Fred ~10 sec/compound<br />
Docking time : Gold not reported
Improvement using consensus<br />
Top ranked pose less than RMS x<br />
RMS < 1<br />
RMS <<br />
1.5<br />
RMS <<br />
2.0<br />
Shapegauss 14% 24% 24%<br />
PLP 10% 10% 9%<br />
Chemgauss 6% 13% 18%<br />
Chemgauss2 -2% 5% 3%<br />
Chemscore 9% 12% 13%<br />
<strong>Screenscore</strong> 13% 13% 13%
Consensus ranking of optimized poses<br />
Best pose in Top 10 pose less than RMS x<br />
RMS < 1 RMS < 1.5 RMS < 2.0<br />
Shapegauss 52% 72% 81%<br />
PLP 53% 76% 85%<br />
Chemgauss 47% 72% 81%<br />
Chemgauss2 52% 72% 81%<br />
Chemscore 51% 73% 84%<br />
<strong>Screenscore</strong> 50% 75% 83%
Fred 2.1 Docking Process<br />
Exhaustive Docking Optimization Consensus<br />
Structure<br />
Scoring<br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
Chemgauss2<br />
Shapegauss<br />
PLP<br />
Chemgauss2<br />
Chemscore<br />
<strong>Screenscore</strong><br />
MMFF<br />
Shapegauss<br />
PLP<br />
Chemgauss2<br />
Chemscore<br />
<strong>Screenscore</strong><br />
* Dashed lines represents that only one path is taken<br />
Shapegauss<br />
PLP<br />
Chemgauss2<br />
Chemscore<br />
<strong>Screenscore</strong><br />
Zapbind<br />
> 10 100 Poses 1 Pose<br />
5 Poses 100 Poses
Enrichment test compounds<br />
PDB Total # Average<br />
MW<br />
Average #<br />
Conformers<br />
Cox2 1cx2 128 365 41<br />
Estrogen 3ert 66 380 121<br />
HIVP 1hvp 18 580 335<br />
RT 1rt2 16 332 119<br />
Thrombin 1ett 80 444 353<br />
Decoys 1037 349 138
M.A.S.C.<br />
Multiple Active Site Comparison<br />
1. Pre-dock ligand into multiple reference active sites<br />
2. Calculate score average and standard deviation in the reference sites<br />
3. Correct score in actual docking runs with the following formula<br />
• Reduces systematic biases in scoring functions<br />
• Pre-dock calculations are expensive but only need to be done once<br />
for a given database<br />
• Can be used with any scoring function
Enrichment Summary w/o MASC<br />
Average of %2, %5 and 10% enrichment<br />
Cox2 Estrogen HIVP rt Thrombin Average<br />
Shapegauss 1.2 10.2 25.4 0.8 5.8 8.7<br />
PLP 4.2 10.2 8.3 3.7 4.9 6.3<br />
Chemgauss 3.5 10.4 14.1 5.0 6.5 7.9<br />
Chemscore 1.7 11.9 3.0 2.9 0.5 4.0<br />
<strong>Screenscore</strong> 5.0 9.9 3.1 3.5 3.4 5.0<br />
Consensus 4.2 11.4 3.1 2.9 2.8 4.9
Enrichment Summary with MASC<br />
Average of %2, %5 and 10% enrichment<br />
Cox2 Estrogen HIVP rt Thrombin Average<br />
Shapegauss 5.4 6.4 17.2 6.5 2.7 7.6<br />
PLP 2.6 8.8 4.1 8.8 4.0 5.6<br />
Chemgauss 4.2 10.5 1.7 7.5 2.6 5.3<br />
Chemscore 3.4 6.4 3.7 9.8 1.4 4.9<br />
<strong>Screenscore</strong> 3.7 8.8 12.0 5.2 2.3 6.4<br />
Consensus 4.7 11.4 11.1 10.8 3.5 8.3
Shapegauss<br />
PLP<br />
Chemgauss<br />
Chemscore<br />
Average Enrichment<br />
Consensus structure<br />
(Fred 2.1)<br />
No Consensus Structure<br />
(Fred 2.0)<br />
Shape<br />
(Fred 1.2)<br />
MASC no MASC MASC No MASC No MASC<br />
7.6 8.7 6.4 8.8 8.6<br />
5.6 6.3 2.9 5.5 6.3<br />
5.3 7.9 3.1 7.4 7.5<br />
4.9 4.0 1.9 3.7 4.0<br />
<strong>Screenscore</strong> 6.4 5.0 3.3 4.1 5.0<br />
Consensus<br />
Scoring<br />
8.3 4.9 5.7 4.1 5.3<br />
*Docking time is ~10sec/molecules, 1Ghz Pentium II
How consistent is the scoring<br />
(average enrichment minus one standard deviation)<br />
Consensus structure<br />
(Fred 2.1)<br />
No Consensus Structure<br />
(Fred 2.0)<br />
Shape<br />
(Fred 1)<br />
MASC no MASC MASC No MASC No MASC<br />
Shapegauss 2.1 -1.4 -0.1 -1.2 -1.5<br />
PLP 2.7 3.5 -0.6 1.7 3.1<br />
Chemgauss 1.6 3.6 -0.1 2.1 1.4<br />
Chemscore 1.7 -0.6 0.6 -1.3 -0.8<br />
<strong>Screenscore</strong> 2.4 2.2 0.0 0.7 2.1<br />
Consensus<br />
Scoring<br />
4.5 1.2 1.7 0.2 1.9<br />
*Docking time is ~10sec/molecules, 1Ghz Pentium II
Consensus MASC results
Fred 2.1 with MMFF and Zap<br />
Exhaustive Docking Optimization Consensus<br />
Structure<br />
Scoring<br />
Shapegauss<br />
PLP<br />
Chemgauss<br />
Chemgauss2<br />
Shapegauss<br />
PLP<br />
Chemgauss2<br />
Chemscore<br />
<strong>Screenscore</strong><br />
MMFF<br />
Shapegauss<br />
PLP<br />
Chemgauss2<br />
Chemscore<br />
<strong>Screenscore</strong><br />
> 10 100 Poses<br />
5 Poses 100 Poses<br />
Shapegauss<br />
PLP<br />
Chemgauss2<br />
Chemscore<br />
<strong>Screenscore</strong><br />
Zapbind<br />
1 Pose<br />
* Dashed lines represents that only one path is taken
Average Results<br />
Average enrichment Average minus standard<br />
deviation enrichement<br />
MASC No MASC MASC No MASC<br />
Shapegauss 4.1 8.0 -1.4 -0.8<br />
PLP 6.6 7.8 1.4 0.4<br />
Chemgauss 5.5 8.4 0.8 -0.4<br />
Chemscore 4.7 5.3 1.8 0.9<br />
<strong>Screenscore</strong> 6.4 7.6 1.0 1.3<br />
Zapbind 5.2 4.3 1.5 0.5<br />
Consensus 7.6 7.2 3.4 2.5<br />
*Docking time is ~20sec/molecules, 1Ghz Pentium II
Overall MASC Zapbind results
Zap can work when others don’t<br />
Thrombin (1ett), % of actives in top x% of database
Conclusion<br />
• Consensus structure improves results<br />
• Consensus scoring improves enrichment on average<br />
• MASC improves results and adds consistency<br />
• Zap can succeed where other functions fail<br />
• Shape works, especially with the right structure<br />
• With consensus structure Zap and MMFF can be<br />
done in reasonable periods of time
Acknowledgments<br />
• Geoff Skillman – enrichment test sets<br />
• Matt Stahl – Some kick butt conformers<br />
• Visualization tools<br />
– Kevin Schmidt<br />
– John Christopher<br />
– Joe Corkery<br />
• Tanja Schulz-Gasch (Roche)<br />
– Test data<br />
– Valuable feedback<br />
• Everyone at <strong>OpenEye</strong>
Estrogen (3ert) Results (PLP opt)<br />
% of actives in top x% of database
HIVP (1hivp) Results (PLP opt)<br />
% of actives in top x% of database
RT (rt2) Results (PLP opt)<br />
% of actives in top x% of database
Cox2 (1cx2) Results (PLP opt)<br />
% of actives in top x% of database
Thrombin (1ett) Results (PLP opt) %<br />
of actives in top x% of database
Estrogen (3ert) Results (MMFF opt)<br />
% of actives in top x% of database
HIVP (1hivp) Results (MMFF opt)<br />
% of actives in top x% of database
RT (rt2) Results (MMFF opt)<br />
% of actives in top x% of database
Cox2 (1cx2) Results (MMFF opt)<br />
% of actives in top x% of database
Thrombin (1ett) Results (MMFF opt)<br />
% of actives in top x% of database
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