Recent improvements in marvin v6 reaction atom mapping and its application to reaction validation in...
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![Page 1: Recent improvements in marvin v6 reaction atom mapping and its application to reaction validation in pharmaceutical el ns](https://reader034.fdocuments.us/reader034/viewer/2022051608/5444286ab1af9f700a8b47d5/html5/thumbnails/1.jpg)
ChemAxon UGM, San Diego, USA 25th September 2013
Recent improvements in Marvin v6: Reaction Atom Mapping and its Application to
Reaction Validation in Pharmaceutical ELNs
Daniel Lowe and Roger Sayle
NextMove Software
Cambridge, UK
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ChemAxon UGM, San Diego, USA 25th September 2013
What is Atom-Mapping?
Mapping algorithm
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ChemAxon UGM, San Diego, USA 25th September 2013
Why Perform Atom-Mapping?
• Assigning roles to reagents
• Normalization of reactions for registration
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ChemAxon UGM, San Diego, USA 25th September 2013
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
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ChemAxon UGM, San Diego, USA 25th September 2013
Example
• I want to find reactions converting an alkene to a cyclopropane so I search for C=C>>C1CC1
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ChemAxon UGM, San Diego, USA 25th September 2013
Why Perform Atom-Mapping?
• Identifying suspect reactions:
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ChemAxon UGM, San Diego, USA 25th September 2013
Chemaxon atom mapping
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ChemAxon UGM, San Diego, USA 25th September 2013
Chemaxon atom mapping
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ChemAxon UGM, San Diego, USA 25th September 2013
Atom mapping modes
• Complete
• Changing
• Matching
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ChemAxon UGM, San Diego, USA 25th September 2013
Methodology
Test set Reactions
Pharmaceutical ELN subset 18,244
ChemReact68 database 67,926
SPRESI database subset 5,230
Reactions extracted from 2008-2011 USPTO patent applications*
562,872
* Lowe, D. M. Automated Extraction of Reactions from the Patent Literature. 243rd ACS National Meeting & Exposition, San Diego, CA, March 27, 2012.
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ChemAxon UGM, San Diego, USA 25th September 2013
MetricS used
• Were all product atoms mapped
– Measures recall
• How many C-C bonds were broken
– Measures precision
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ChemAxon UGM, San Diego, USA 25th September 2013
Ability to map all product atoms
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PharmaELN ChemReact68 SPRESI USPTO
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ChemAxon UGM, San Diego, USA 25th September 2013
c-c bonds broken
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ChemDraw 12
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ChemAxon UGM, San Diego, USA 25th September 2013
Marvin 5.10
ChemDraw 12
Marvin 6.0
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ChemAxon UGM, San Diego, USA 25th September 2013
Speed Comparison
*Comparison performed on the PharmaELN dataset on an i7-2600
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ChemAxon UGM, San Diego, USA 25th September 2013
Difficult cases
ΔT
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ChemAxon UGM, San Diego, USA 25th September 2013
Areas for improvements: Implicit stoichiometry
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ChemAxon UGM, San Diego, USA 25th September 2013
Areas for improvements: many choices for reactant atom mapping
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ChemAxon UGM, San Diego, USA 25th September 2013
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Marvin6 + ChemDraw12
Consensus Result*
Consensus Methods
* Marvin 6.0 + ChemDraw12 + 2 variants of GGA’s Indigo toolkit + InfoChem ICMap + Pipeline Pilot + MDL Cheshire
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ChemAxon UGM, San Diego, USA 25th September 2013
Beyond atom mapping
• Missing reactants (often for routine reactions)
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ChemAxon UGM, San Diego, USA 25th September 2013
Beyond atom mapping
• Change of stereoisomer or chiral resolution
(E)-3-{8-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-2-methoxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoic acid (1 mg) was dissolved in CDCl3 (0.5 ml) and irradiated with light from a fluorescent lamp
for 19 hours . The solvent was evaporated to obtain the title compound (1 mg).
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ChemAxon UGM, San Diego, USA 25th September 2013
Atom mapping + classification
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Combined withNameRXN
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ConsensusResult
Verified / Recognised
by NameRXN
(71%)
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ChemAxon UGM, San Diego, USA 25th September 2013
conclusions
• Marvin v6’s atom mapping algorithm provides large improvements in recall, precision and speed over v5
• Atom mapping in some cases isn’t as simple as finding a maximum common subgraph mapping
• Classification algorithms can be useful for the validation of some reactions
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ChemAxon UGM, San Diego, USA 25th September 2013
acknowledgements
• Zsolt Mohacsi and Istvan Rabel, ChemAxon
• Ed Griffen and Nick Tomkinson, AstraZeneca
• Andrew Wooster, GSK
• Hans Kraut, InfoChem
• Thank you for your time.