Evaluating the Quality and Performance of Automatic Atom Mapping Algorithms

Presented in the Open Notebook Science/Open Chemistry/Electronic Lab Notebook symposium. 20th August 2012, Philadelphia ACS

Evaluating the Quality and
Performance of Automatic Atom
Mapping Algorithms

Daniel Lowe and Roger Sayle
NextMove Software
Cambridge, UK

ACS National Meeting, Philadelphia, USA 20th August 2012

What is Atom-Mapping?

Mapping
algorithm

ACS National Meeting, Philadelphia, USA 20th August 2012

Why Perform Atom-Mapping?

• Assigning roles to reagents

• Normalization of reactions for registration

ACS National Meeting, Philadelphia, USA 20th August 2012

Why Perform Atom-Mapping?

• More precise database searches
– Solvents/catalysts can be distinguished from
reactants
– Allows the relationship between the reactant
atoms and product atoms to be made explicit

ACS National Meeting, Philadelphia, USA 20th August 2012

Example
• I want to find reactions converting an alkene
to a cyclopropane so I search for C=C>>C1CC1

ACS National Meeting, Philadelphia, USA 20th August 2012

Why Perform Atom-Mapping?

• Identifying suspect reactions:

ACS National Meeting, Philadelphia, USA 20th August 2012

Qualities to look for in an atom
mapping algorithm
• Chemically plausible atom mappings
• Ability to distinguish genuine reactants from
solvents/catalysts
• Support for unbalanced reactions
– Side product not specified
– Reactant stoichiometry > 1
• Fast run-time

ACS National Meeting, Philadelphia, USA 20th August 2012

Algorithms Evaluated

Vendor:Program Version
ChemAxon:Marvin 5.10.1
GGA:Indigo 1.1
InfoChem:ICMAP 5.10
PerkinElmer:ChemDraw Ultra 12.0

ACS National Meeting, Philadelphia, USA 20th August 2012

Methodology

Test set Reactions
Pharmaceutical ELN subset 18,244
ChemReact68 database 67,926
SPRESI database subset 5,230
Reactions extracted from 2008- 562,872
2011 USPTO patent applications*

* Lowe, D. M. Automated Extraction of Reactions from the Patent Literature.
243rd ACS National Meeting & Exposition, San Diego, CA, March 27, 2012.

ACS National Meeting, Philadelphia, USA 20th August 2012

Methodology-cont.

• Reaction SMILES were used as input and
output for all algorithms bar ICMAP
• Input and output was converted to and from
RDF for use with ICMAP
• Indigo was ran with its default configuration
and more lenient settings for matching
valences, charges and bond orders
• Marvin was configured to use its best
quality mapping strategy
ACS National Meeting, Philadelphia, USA 20th August 2012

Ability to map all product atoms

ACS National Meeting, Philadelphia, USA 20th August 2012

c-c bonds broken

ACS National Meeting, Philadelphia, USA 20th August 2012

Speed Comparison

Average 1.7 3.6 1.6 4.0
reagents per
reaction
ACS National Meeting, Philadelphia, USA 20th August 2012

Simple mappings

Marvin/ChemDraw/Indigo/ICMAP
ACS National Meeting, Philadelphia, USA 20th August 2012

More complicated Mappings

Marvin

ChemDraw

ACS National Meeting, Philadelphia, USA 20th August 2012

More complicated Mappings

Indigo

ICMAP

ACS National Meeting, Philadelphia, USA 20th August 2012

Reuse of reactants

ACS National Meeting, Philadelphia, USA 20th August 2012

Reuse of reactants

Marvin
ACS National Meeting, Philadelphia, USA 20th August 2012

Reuse of reactants

ChemDraw
ACS National Meeting, Philadelphia, USA 20th August 2012

Reuse of reactants

Indigo
ACS National Meeting, Philadelphia, USA 20th August 2012

Reuse of reactants

ICMAP
ACS National Meeting, Philadelphia, USA 20th August 2012

Single Atom Mapping

ICMAP/Marvin

ChemDraw/Indigo

ACS National Meeting, Philadelphia, USA 20th August 2012

Bugs and quirks

• Marvin
– 2 unsuccessful mappings produced unchecked
exceptions rather than checked exceptions
• ChemDraw
– Hydrogen on aromatic atoms missing in SMILES
output
• Indigo
– Calculation of valency fails for aromatic sulfur

ACS National Meeting, Philadelphia, USA 20th August 2012

Bugs and quirks

• ICMAP
– Single atom products are interpreted as empty
molecules or occasionally replaced by a product
from a previous reaction (bug reported)
– Input files must be < 2gb and use dos line endings

ACS National Meeting, Philadelphia, USA 20th August 2012

conclusions

• ICMAP produced the best quality mappings on
the tested sets

• Atom mapping isn’t as simple as finding a
maximum common subgraph mapping

• In all the algorithms there were aspects that
could be improved to yield appreciable
benefits
ACS National Meeting, Philadelphia, USA 20th August 2012

acknowledgements

• Ed Griffen and Nick Tomkinson, AstraZeneca.
• Andrew Wooster, GSK.
• Hans Kraut, InfoChem

• Thank you for your time.

ACS National Meeting, Philadelphia, USA 20th August 2012

The document evaluates and compares the performance of five automatic atom mapping algorithms: Pipeline Pilot, Marvin, Indigo, ICMAP, and ChemDraw. It finds that ICMAP produced the best quality mappings, correctly mapping all product atoms. However, all the algorithms showed room for improvement, such as in handling more complex mappings with reactant reuse or single atom mappings. The document concludes atom mapping is more complex than maximal common subgraph matching and presents results on various algorithms' performance using several benchmark reaction datasets.

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