Reaction Representation and Structure Transformation with Ambit-SMIRKS.
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Reaction Representation and Structure Transformation with Ambit-SMIRKS.

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Best poster award at http://www.opentox.org/meet/opentoxeu2013/opentoxeuro13awards ...

Best poster award at http://www.opentox.org/meet/opentoxeu2013/opentoxeuro13awards

http://www.opentox.org/meet/opentoxeu2013/opentoxeu2013posters/

7. Reaction Representation and Structure Transformation with Ambit-SMIRKS. Application in Metabolite prediction
Ambit-SMIRKS is a new extension of the Ambit-SMARTS Java library [1], both part of the Ambit2 [2] project. The modules are implemented on top of the Chemistry Development Kit (CDK) [3]. Ambit-SMIRKS performs two main tasks: (1) parsing of SMIRKS linear notations into internal reaction (transformation) representations based on CDK objects and (2) application of the stored reactions against target molecules for actual transformation of the target chemical objects. The transformations can be applied on various sites of the target molecule in several modes: single, non-overlapping, non-identical, non-homomorphic or externally specified list of sites. Ambit-SMARTS implements the entire SMARTS language specification as defined by Daylight, plus additional syntax extensions to make software compliant with SMARTS modifications made by third party software packages such as OpenEye, MOE and OpenBabel. The SMIRKS library utilizes the SMARTS parser and the efficient substructure searching algorithm implemented within Ambit-SMARTS package [1]. Typically most SMIRKS implementations support SMILES plus simple SMARTS syntax features. However, Ambit-SMIRKS module supports full SMARTS syntax for reactions specification. The SMIRKS module is used to enable metabolite predictions in Toxtree (since version 2.5.0) [4], once the site of metabolism is predicted by SMARTCyp [5]. Toxtree is a flexible and user-friendly open-source application that predicts various kinds of toxic effects, mostly by applying structural alerts, arranged in a decision tree fashion. SMARTCyp (Cytochrome P450-Mediated Drug Metabolism) model is originally developed by Patrik Rydberg et al [5] and was included as Toxtree module since Toxtree 2.1.0. Ambit-SMIRKS functionality is available as a Java library as well as OpenTox Algorithm API compatible Web service. We also welcome testing the SMIRKS at the web page http://apps.ideaconsult.net:8080/ambit2/depict/reaction.

References
[1] N. Jeliazkova, N. Kochev, AMBIT-SMARTS: Efficient Searching of Chemical Structures and Fragments, Mol. Inf., 30: 707–720, 2011
[2] Jeliazkova N., Jeliazkov V. AMBIT RESTful web services: an implementation of the OpenTox application programming interface, Journal of Cheminformatics 2011, 3:18, doi:10.1186/1758-2946-3-18.
[3] C. Steinbeck, Y. Han, S. Kuhn, O. Horlacher, E. Luttmann, E. Willighagen, The Chemistry Development Kit (CDK):  An Open-Source Java Library for Chemo- and Bioinformatics, J. Chem. Inf. Comput. Sci., 43: 493–500, 2003
[4] http://toxtree.sourceforge.net
[5] P. Rydberg, D. Gloriam, J. Zaretzki, C. Breneman, L. Olsen, SMARTCyp: A 2D Method for Prediction of Cytochrome P450-Mediated Drug Metabolism

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Reaction Representation and Structure Transformation with Ambit-SMIRKS. Reaction Representation and Structure Transformation with Ambit-SMIRKS. Document Transcript

  • Reaction Representation and Structure Transformation with Ambit-SMIRKS. Application in Metabolite Prediction Nina Jeliazkova a*, Nikolay T. Kochev b, Patrik Rydbergc, Svetlana Avramova b a) Ideaconsult Ltd, 4 A. Kanchev str., Sofia 1000, Bulgaria b) University of Plovdiv, Department of Analytical Chemistry and Computer Chemistry, 24 Tsar Assen St., Plovdiv, Bulgaria c) Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen *To whom correspondence should be addressed. e-mail: nina.jeliazkova@gmail.com, twitter: @10705013 Ambit-SMIRKS is a new extension of the Ambit-SMARTS Java library [1], both part of the Ambit2 [2] project. Implemented on top of Chemistry Development Kit [3], the SMIRKS module is used to enable metabolite predictions in Toxtree [4], once that site of metabolisms are predicted by SMARTCyp [5]. Ambit-SMIRKS main tasks: Ambit-SMARTS basic features: (1) Parsing of SMIRKS linear notations into internal reaction (transformation) representations based on CDK objects (2) Application of the stored reactions against target molecules for actual transformation of the target chemical objects (1) SMIRKS Parsing Effective representation of SMARTS Queries based on CDK (full Daylight syntax) (2) Fast structure isomorphism /mapping/ (3) Support of recursive SMARTS (4) Syntax extensions Transformation application SMARTS searching Input SMIRKS: [N:1]1[C:2][C:3]=[C:4][C:5]1>>[N:1]1[C:2]=[C:3][C:4]=[C:5]1 Single mode Input Target Molecule (SMILES, InChI, CML, MOL file) HN N OH 1 N Parse Reactant SMARTS Parse Mapping CDK object 4 HO 1 2 HN NH 5 N N N NH Reactant fragment found at 3 positions NH N NH N NH NH 3 Transformation mapping modes N N Non-identical mode OH OH The transformations can be applied on various sites of the target molecule in several modes: (1) single (2) non-overlapping, (3) non-identical, (4) non-homomorphic or (5) externally specified list of sites. - C 2 N NH - Work with mapping combinations (equivalent to the non-overlapping mode for this structure) C NH 4 HN1 NH Non-overlapping mode 3 2 NH N OH CDK object 3 N N HO [N:1]1[C:2]=[C:3][C:4]=[C:5]1 Parse Product SMARTS HN NH NH Parse SMIRKS components [N:1]1[C:2][C:3]=[C:4][C:5]1 http://tinyurl.com/testreaction NH 5 Potential incorrect structure due to mappings collision N Reaction mapping object OH Basic metabolic reactions in SMARTCyp implemented by Toxtree SMIRKS Application in metabolite generation HO Aliphatic hydroxylation (1) Toxtree is an open-source application that predicts various kinds of toxic effects, mostly by applying structural alerts, arranged in a decision tree fashion H3C H O O-dealkylation H3C CH3 H3C N H H3C O Thioester bond breaking CH3 OH R S R OH + R H3C CH3 1 SH O Alcohol oxidation H3C CH3 N NH H3C CH3 H3C Dioxolane demethylenation O O S CH3 H3C - H3C O H3C H3C Desulphurization of phosphor OH H3C O S HN H3C CH2 O S Dihydropyrrole aromatization N O Aldehyde oxidation O + OH S-oxidation CH3 H3C HO O S H N Aromatization of dihydropyridines H2C H O O S-oxidation H3C 1 CH3 N-dealkylation N O R Ambit-SMIRKS generated metabolites N-oxidation CH3 N CH3 H3C CH3 O N Amine hydroxylation H3C CH3 H3C Epoxidation O CH3 (2) SMARTCyp (Cytochrome P450-Mediated Drug Metabolism) model is developed by Patrik Rydberg et al [5] and is included as Toxtree module since Toxtree 2.1.0. Sites of metabolism as predicted by SMARTCyp Aromatic hydroxylation CH3 H3C CH3 http://toxtree.sourceforge.net/predict/ Application of Ambit-SMIRKS module for prediction of Omeprazole metabolism OH CH3 H3C O CH3 HN S P CH3 H3C H3C O P CH3 Importance of metabolism prediction H N Virtual safety testing (Ames models) HN N N CH3 Cl N N N N (1) Model 1 metabolite + (3) - Model 2 Model 3 H3C O H N NH References: [1] N. Jeliazkova, N. Kochev, AMBIT-SMARTS: Efficient Searching of Chemical Structures and Fragments, Mol. Inf., 30: 707–720, 2011 [2] Jeliazkova N., Jeliazkov V. AMBIT RESTful web services: an implementation of the OpenTox application programming interface, Journal of Cheminformatics 2011, 3:18, doi:10.1186/1758-2946-3-18. [3] C. Steinbeck, Y. Han, S. Kuhn, O. Horlacher, E. Luttmann, E. Willighagen, The Chemistry Development Kit (CDK):  An Open-Source Java Library for Chemo- and Bioinformatics, J. Chem. Inf. Comput. Sci., 43: 493–500, 2003 [4] http://toxtree.sourceforge.net [5] P. Rydberg, D. Gloriam, J. Zaretzki, C. Breneman, L. Olsen, SMARTCyp: A 2D Method for Prediction of Cytochrome P450-Mediated Drug Metabolism, ACS Med. Chem. Lett., 2010, 1 (3), pp 96-100 N metabolite (2) N H3C 0 1 0 Norclozapine 0 1 0 Clozapine N-oxide 1 1 0 4 Hydroxyclozapine 0 1 0 OH N Cl Clozapine 2 H N N N 1 3 Cl metabolite Toxic metabolites are formed in some cases leading to unwanted adverse effects. Safety testing of metabolites has become a requirement according to the guidance for industry issued by regulatory institutions. (4) Predictions via AMBIT web services (OpenTox API ) http://ambit.sf.net