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

1. 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