Substructure Search Face-off

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Cambridge Cheminformatics Network Meeting, Cambridge, 27th May 2015
Substructure Searching
Face-off
John May and Roger Say...

Molecular Identity
is foo the same as bar?
Substructure
is foo part of bar?
Chemical Similarity
how much is foo like bar?
...

SUBSTRUCTURE SEARCH
Some of the many uses:
• Fragment-based lead discovery
• Murcko Scaffolds
• Matched pairs
• Functional...

ANATOMY OF A SUBSEARCH
0008800040008020 CCO
1000000050000028 NCC
5008a04040008020 CCCCO
0000000040000024 CCl
0000080000040...

WHY CAN IT FEEL SLOW?
Identity and Similarity Search
different queries, similar amount of work
Substructure Search
differe...

STRATEGIES?
Parallelisation
resource contention from multiple users
Limit query count (first 10)
must decide which ones ar...

EXISTING BENCHMARKS
Several tools publish isolated performance figures
and should be commended.
“what performance can you ...

OUR BENCHMARK:
COUNT TOTAL
NUMBER OF HITS

TARGET DATABASE
Needed moderate size collection
ChEMBL ~1.5 mil, too easy, fits easily in a memory cache
PubChem Compound ...

QUERIES
Structure Query Collection (SQC)
3,488 BindingDB_substructure queries
3,342 connected, 121 fragments
User generate...

QUERIES
Duplicates due to aromaticity or hydrogens
[H]C1=CN=CN=C1[H] pyrimidine
[H]C1=CN=CN=C1 pyrimidine
C1=CN=CN=C1 pyri...

KEY Type Chemistry Storage FORMAT
arthor standalone NextMove Flatfile Serialised
bingo-pgsql cartridge Indigo PostgreSQL S...

Name Type Chemistry Storage
Pinpoint Cartridge Dotmatics Oracle
Direct Cartridge BIOVIA/Accelrys/MDL Oracle
Accord Cartrid...

Name Type Chemistry Storage
ChemFP standalone Multiple FPS/BFPS in-memory
Similr standalone ? MongoDB
Data Warrior standal...

CHANGES FROM
“OUT OF THE BOX”
MyChem and RDKit Lucene
- fingerprint screen workaround
- OB FP2 and Avalon FP, no bits ≠ no...

MEASUREMENT IS NOT PROPHECY1
Large number of variables
Time taken for this benchmark, with these tool versions,
on a machi...

3342 Queries
6996230 TARGETS
≤23,381,400,660
MATCHES LATER

EXCLUDED QueRIES
19 queries skipped in one or more tools
3,323/3,342 that were executed by all
2 Non-terminal hydrogens
C1...

RETRIEVAL DIFFERENCES
“We demand rigidly defined areas of doubt and
uncertainty!”
CH3
CH3
o-xylene

RETRIEVAL DIFFERENCES
“We demand rigidly defined areas of doubt and
uncertainty!”
Somewhere between 440,901 and 529,386
rd...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
90%
99%
1s 10s 30s1m 5m
many queries,
r...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
rdcart
rdsmigrep
90%
99%
1s 10s 30s1m 5m

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
rdcart
rdsmigrep
90%
99%
1s 10s 30s1m 5...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
rdcart
rdluc
rdsmigrep
90%
99%
1s 10s 3...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
bingo-orcl
bingo-pgsql
90%
99%
1s 10s 3...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
bingo-orcl
bingo-nosql
bingo-pgsql
90%
...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
jcart-st
jcart
90%
99%
1s 10s 30s1m 5m
...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
jcart-st
jcart
bingo-orcl
bingo-pgsql
9...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
fastsearch
mychem
pgchem
90%
99%
1s 10s...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
fastsearch
mychem
pgchem
90%
99%
1s 10s...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
fastsearch
mychem
pgchem
rdcart
90%
99%...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
tripod-ss
fastsearch
mychem
pgchem
rdca...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
tripod-ss
jcart-st
jcart
rdcart
90%
99%...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
tripod-ss
orchem
fastsearch
rdluc
90%
9...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
bingo-nosql
bingo-nosql-clean
90%
99%
1...

OTHER CONSIDERATIONS
What are the hits? o-xylene example
How do they scale?
• Index, tree-based indexes will have many
mor...

BENCHMARK SUMMARY
Many tools have reasonable performance for most
queries but are hindered by their worst cases.
Minimal d...

FINGERPRINT PERFORMANCE
Much work has been done on optimising fingerprints
Screen performance measured for several of the ...

AN EfFICIENT
ATOM-MATCH
Arthor
(codename)
• Query optimisation
• Database preprocessing
• Efficient binary representation
...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
3323
orchem
fastsearch
jcart
bingo-nosql
bin...

FINGERPRINTING MATERS
Arthor - 0% screen-out
23,290,449,670 atom-matches
Bingo - 98.63% screen-out
319,079,160 atom-matche...

FINGERPRINTING MATERS
Fingerprint Length Density Time False
NEGATIVES
arthor - - 27m35s -
+rdpath 2048 61.90% 2m52s
(x9.5)...

1
10
100
1000
100
101
102
103
104
105
106
107
QueriesNotFinished(n)
Time (ms)
90%
99%
1s
arthor
rdpath
maccs
dalke353
jpat...

CONCLUSIONS
Fast searching depends on many factors
• index data-structure
• fingerprint type
• molecule representation
• a...

ACKNOWLEDGEMENTS
Daniel Lowe and Noel O’Boyle, NextMove Software
Andrew Dalke
- assembling Structure Query Collection (SQC...

Further optimisation and keeping file open: 36 s including
inverted index FP screen, single threaded:
1
10
100
1000
100
10...

Some FALSE NEGATIVES
Most false negatives are due to Kekulisation/Aromaticity.
Typically when reading SMILES a tool will a...

Some FALSE NEGATIVES
OO
CH3
OO
CH3
OO
CH3
OO
CH3
Kekulise Aromatise
JChem, RDKit
Open Babel, CDK, OEChem
Does have
o-xylen...

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