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WIREs Comput Mol Sci
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Automatic reaction mapping and reaction center detection

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Abstract A reaction center is the part of a chemical reaction that undergoes changes, the heart of the chemical reaction. The reaction atom–atom mapping indicates which reactant atom becomes which product atom during the reaction. Automatic reaction mapping and reaction center detection are of great importance in many applications, such as developing chemical and biochemical reaction databases and studying reaction mechanisms. Traditional reaction mapping algorithms are either based on extended‐connectivity or maximum common substructure (MCS) algorithms. With the development of several biochemical reaction databases (such as KEGG database) and increasing interest in studying metabolic pathways in recent years, several novel reaction mapping algorithms have been developed to serve the new needs. Most of the new algorithms are optimization based, designed to find optimal mappings with the minimum number of broken and formed bonds. Some algorithms also incorporate the chemical knowledge into the searching process in the form of bond weights. Some new algorithms showed better accuracy and performance than the MCS‐based method. WIREs Comput Mol Sci 2013, 3:560–593. doi: 10.1002/wcms.1140 This article is categorized under: Computer and Information Science > Chemoinformatics

The concept of MCS. The substructures contained in the original structures are highlighted in bold.

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Latendresse et al. reaction mapper produced two reaction mappings for the Diels–Alder reaction shown in Figure . Latendresse et al. program did not mark the bond order changes. Their program marked the broken and formed bonds in black. (Reproduced with permission from Ref 76.)
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Latendresse et al. reaction mapper produced correct reaction mapping for R00053 (see Figure ). Latendresse et al. program did not mark the bond order changes. Note: their program marked the broken and formed bonds in black. (Reproduced with permission from Ref 76.)
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DREAM found six AAMs for reaction EC 2.6.1.28. Two of them are shown in this Figure. (1) An incorrect AAM. (2) A chemically correct AAM. (Adapted from Ref 76. Copyright 2012, American Chemical Society.)

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R00652 methionine: glyoxylate aminotransferase reaction. (1) The atom mapping found by the A* algorithm requires only one bond broken and one bond formed; but this mapping is incorrect. (2) The atom mapping found by the MCS algorithm requires four operations: two bonds broken and two new bond formations; this is the correct reaction mechanism. The MCSs in (2) are highlighted in bold. The reacting bonds in both (1) and (2) are marked in red. (Adapted from Ref 55. Copyright 2004, Mary Ann Liebert, Inc.)

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(1) A special type of chemical reactions with two reactants and two products. All reaction structures are acyclic and can be split into two parts by cutting one bond (‘–’ corresponds to a cut). (2) A directed cycle of length 4 that is built from reaction (1). Chemical cuts X–A, Y–B, X–B, Y–A separately correspond to directed edges (A, X), (B, Y), (X, B), and (Y, A). (3) Example of a reaction instant that has the form (1). This reaction is catalyzed by a transaminase. There are three possible pairs for (A, B), where (A1, B1) is the most plausible. (Adapted from Ref 55. Copyright 2004, Mary Ann Liebert, Inc.)

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The reaction RXN00048 of BioPath. Note 1: Hydrogen atoms with no stereo bond connections are not shown here. Note 2: In BioPath, all reactants are grouped into one structure representation, and so are the products. (Adapted from Ref 52. Copyright 2008, American Chemical Society.)

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Two reactions (1) and (2) are identical with the corresponding reactions in Figure except that the largest common substructure between the reactant and the product that does not include reacting bonds were highlighted with the bold bonds. The reacting bonds are highlighted in red and also marked with the hash marks.

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Isochorismate synthase (RXN00053). (a) The reaction centers marked in the original BioPath database. (b) The solution of the ITSE method. Note: The reacting bonds are highlighted in red. (Adapted from Ref 52. Copyright 2008, American Chemical Society.)

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The structures for reactant R and product P. (Adapted from Ref 13. Copyright 1988, Elsevier.)

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(1) and (2) are two possible reaction sites (highlighted in red) of the Favorskii rearrangement. (3) The reaction intermediate that contains the cyclopropanone substructure. (Adapted from Ref 13. Copyright 1988, Elsevier.)

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(1) The first step of the Pechmann reaction. (2) Two MCSs. (3) The reaction with reacting bonds highlighted in red, and the phenol MCS highlighted in bold. (Adapted from Ref 13. Copyright 1988, Elsevier.)

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(1) The Diels–Alder reaction that consists of two reactants and one product. (2) The reaction sites recognized are marked in red, and the MCSs are highlighted in bold. (Adapted from Ref 13. Copyright 1988, Elsevier.)

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(1) Reaction. (2) MCS. (3) The reaction with the reacting bonds highlighted in red, and the MCSs marked in bold. (Adapted from Ref 39. Copyright 1981, American Chemical Society.)

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(1) Reaction. (2) MCS. (3) The reaction with reacting bond highlighted in red and the MCSs are in bold.

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(1) Reaction. (2) The reaction sites obtained using the Lynch–Willett method. (3) MCS. (4) The reaction with reaction centers highlighted in red and also with the hash marks, and the MCSs are highlighted in bold. Note: In reaction site (2) and the MCS (3), two unnumbered carbon atoms have ‘free’ valences of one and three, respectively. (Adapted from Ref 39. Copyright 1981, American Chemical Society).

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(1) Reaction. (2) MCS. (3) The reaction with reacting bonds highlighted in red. The MCSs in (3) are highlighted in bold. (Adapted from Ref 39. Copyright 1981, American Chemical Society.)

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Analysis of an unbalanced reaction. (1) Original reaction. (2) The reaction with the AAM marked and the reaction bonds highlighted in red and also with hash marks. (Adapted from Ref 35. Copyright 1988, Springer.)

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The reaction (1) in this figure is identical to Figure (1) except that the product structure was flipped over. The Automapper generated the same result [shown in (2)] as that in Figure (2). The reacting bonds are highlighted in red.

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An example showing that whether the stereoconfiguration of a stereogenic center is changed cannot be determined by simply mapping an UP bond to an UP bond or a DOWN bond to a DOWN bond. (1) Original reaction. (2) Automapper results: atom .2.'s stereoconfiguration is retained, whereas atom .5.'s reversed. Reacting bonds are highlighted in red.

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Automapper found the correct AAM and reaction center for this simple, unbalanced reaction. Note: The reacting bonds are marked in red and also with hash marks.

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(1) The Diels–Alder reaction. (2) Two sets of MCSs. (3) Two possible solutions based on the MCSs: the incorrect solution (left) and correct solution (right). (4) The output solution from the Automapper program. In both (3) and (4), the reacting bonds are highlighted in red and also with hash marks. The MCSs in (4) are highlighted in bold. (Adapted from Ref 35. Copyright 1988, Springer.)

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In this reaction, the invalid equivalence between reactant atom 16 and product atom 25 is obtained. (Adapted from Ref 17. Copyright 1978, American Chemical Society.)

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This reaction is an example that contradicts the assumption that equal EC values correspond to identical substructures. The substructures obtained after 4th iteration are highlighted in bold. (Adapted from Ref 17. Copyright 1978, American Chemical Society.)

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The EC‐MCS‐based procedure to find reaction center (marked in red). (Adapted from Ref 17. Copyright 1978, American Chemical Society.)

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This reaction cannot be handled because the reactant and product are too small, and thus no pairs of atoms have a matching radius that is greater than 1. (Adapted from Ref 17. Copyright 1978, American Chemical Society.)

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Reactions that lead to ambiguous mappings cannot be processed. (Adapted from Ref 17. Copyright 1978, American Chemical Society.)

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The bonds attached to the outermost atoms (r6, p6) are differently oriented in the two structures. These two atoms are reacting atoms and thus should not be deleted. The matched substructures are marked using ellipses. The reaction center is highlighted in red. (Adapted from Ref 17. Copyright 1978, American Chemical Society.)

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Example of the calculation of EC values in the Morgan algorithm.

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