Screen3D: A Ligand-based 3D Similarity
Search without Conformational Sampling
Wei Deng (David), Adrian Kalaszi
International Conference and Exhibition on
Computer Aided Drug Design & QSAR
Oct 29th, 2012
Chicago, IL, USA
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Wide Range of Functionalities
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in 3D
3D Structure generation – released in 2002
3D Alignment – released in 2009
3D Similarity – ligand based virtual screening 2010 Q3
multi-core support by 2012 Q4 (version 5.12)
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Example: Thrombin inhibitors
1dwc 1dwd
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Quaternion Fit
Two molecules: translate & rotate one as rigid molecule
Pros:
Minimize RMSD on selected atom pairs (best alignment)
Fast (one step) – analytically solving the equation
Cons:
No flexibility
Need to know the atom mapping
EA. Coutsias et. al, J Comput Chem 25: 1849–1857, 2004
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Flexibility: dihedral angels are optimized
Alternate between quaternion and conformation optimization
Pros:
Very fast
Robust: usually finds the best alignment
Cons:
Two molecules per alignment
Still need to solve the atom/atom mapping
Quaternion & Flexibility Hybrid
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Calculations before Atom-atom Match
Select atoms
Colors (extended atom types / pharmacophore types )
Topological features (e.g.: longest chain start/end/center)
Ring centers (aromatic, aliphatic)
Calculate
Min/max internal distance ranges
Atomic histograms for selected atoms
Once in the lifetime for every molecule
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Min and Max Distance
info
Watch the video here: http://www.youtube.com/watch?v=FgMsvDmtGkA
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Atomic Histograms
d1-min
d1-max
1 2 3 4 5 6 7 8 9 10 11 12
binned distribution of distance 1 2 3 4 5 6 7 8 9 10 11 12
binned distribution of distance
1 2 3 4 5 6 7 8 9 10 11 12 13 1 2 3 4 5 6 7 8 9 10 11 12 131 2 3 4 5 6 7 8 9 10 11 12 13
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Distance Range Tanimoto
d2-min
d2-max
d1-min
d1-max
T=
),min(),max(
),max(),min(
min2min1max2max1
min2min1max2max1
dddd
ddddT
For atom pair comparison
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Triangle Inequality
B
A
C C’
B’
A’
X= common range between AB and A’B’
= (distance range of AB) ∩ (distance range
of A’B’)
Y= common range between AC and A’C’
Z= common range between BC and B’C’
Then they must follows:
X+Y > Z
X+Z > Y
Y+Z > X
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Find the best atom mapping between two molecules
Pairwise search:
1. Same colors of atoms for the pairs
2. Distance ranges OK for any pairs of mapped atoms
3. Triangle inequality for any triplet of maps
4. Quaternion Flexible Hybrid Alignment
Guaranteed: No good solution from the conformational space is lost!
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Example: Thrombin inhibitors
Same colors 6,981,488
After filtering by distance range & triangle inequality 542
1dwc 1dwd
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Output after 3D alignment
1. Atom/atom mapping
2. Molecules aligned
3. SCORE: Tanimoto of atomic histograms of the mapped atoms
Current version use default scoring weights (1, 0)
It’s possible to add customized weights according to the
atom colors
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Test 1 on DUD
ADA Adenosine deaminase 39/927
CDK2 Cyclin dependent kinase 2 72/2074
DHFR Dihydrofolate reductase 410/8367
ER Estrogen receptor antagonist 39/1448
FXA Factor Xa 146/5745
HIVRT HIV reverse transcriptase 43/1519
NA Neuraminidase 49/1874
P38 P38 mitogen activated protein kinase 454/9141
THR Thrombin 72/2456
TK Thymidine kinase 22/891
TRY Trypsin 49/1664
Giganti et al. J. Chem. Inf. Model. 2010, 50, 992
ROCS
Surflex-sim
FlexS
ICMsim
DOCK
Surflex-Dock
FRED
FlexX
ICM
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Test 1 on DUD
1% Enrichment
0
5
10
15
20
25
30
35
40
ADA CDK2 DHFR ER FXA HIVRT NA P38 thrombin TK trypsin
Perc
en
t o
f th
e a
cti
ves f
ou
nd
Surflex-sim
ROCS
FlexS
ICMsim
CXN-H
Giganti et al. J. Chem. Inf. Model. 2010, 50, 992
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Test 1 on DUD
0
5
10
15
20
25
30
% o
f th
e a
cti
ves r
etr
iev
ed
Average of 1% Enrichments
Giganti et al. J. Chem. Inf. Model. 2010, 50, 992
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Test 1 on DUD
0
10
20
30
40
50
60
70
80
90
100
% o
f th
e a
cti
ves r
etr
iev
ed
Average of 10% enrichments
Giganti et al. J. Chem. Inf. Model. 2010, 50, 992
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Test 1 on DUD
Speed
average time per compound (s)
CXN-H 0.07
ROCS 0.5
FRED 1.0
ICMsim 2.4
Surflex-sim 6.7
FlexS 6.9
Surflex-dock 14.6
FLEXX 15.6
ICM 17.7
Intel Xeon 2.4 GHz
Intel Q6600 2.4 GHz
Giganti et al. J. Chem. Inf. Model. 2010, 50, 992
0
5
10
15
20
25
30
35
40
45
50
EF1%
Venkatraman et. al. J. Chem. Inf. Model. 2010, 50, 2079–2093
Test 2 on DUD
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
AUC
Venkatraman et. al. J. Chem. Inf. Model. 2010, 50, 2079–2093
Test 2 on DUD
Calculation Time
• Xeon [email protected], 2x8 cores
• DUD: 128374 structures
• Total time: 212 minutes
• 99 ms/molecule (38ms/molecule with distance range)
Test 2 on DUD
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Conclusion
Screen3D:
Further developments: improve scoring
Comparable to other methods
Fast screening
Evaluators are welcome!
BACKUP SLIDES
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Flexible Alignment
Function
atomic coordinates f(x)
Gradient f(x) /
Kinematics: infinitesimal rotational tensor
http://mathworld.wolfram.com/InfinitesimalRotation.html
Hurst, J. Chem. Inf Comput. Sci. 1994, 34, 190-196
MDS-CG (Multi-Dimensional Search in Conjugate Gradient)
Farkas, Ö., Schlegel, H. B. J. Mol. Struct.-Theochem 2003, 666, 31-39.
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Experiment
Watch the video here: http://www.youtube.com/watch?v=22lfa5HeCts
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Internal Distances
0
1
2
3
4
5
6
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 65
rms
d
(An
gstr
om
)
molecule #
distance
coordinate
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Distances between Molecules
Function atomic coordinates or distances f(x)
Gradient f(x) /
Add six degrees of freedom on molecules that we wish to
translate (3) & rotate (3)
Optimization on mixed internal coordinate / Cartesian domain
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Jump to external distances
Watch the video here: http://www.youtube.com/watch?v=zNtxblx0-Dw
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Jump to external distances
Watch the video here: http://www.youtube.com/watch?v=8KJqz5Emco0
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Jump to external distances
Watch the video here: http://www.youtube.com/watch?v=kXfoukkAmQQ
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