Irredundant generation of isomeric molecular structures with some known fragments

Journal of Chemical Information and Computer Sciences

Volumn 38, Issue 1, 1998, Pages 8-22

  Molchanova, Marina S ^a   Zefirov, Nikolai S ^a  

^a N D ZELINSKY INSTITUTE OF ORGANIC CHEMISTRY   (Russian Federation)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0002522622     PISSN: 00952338     EISSN: None     Source Type: Journal    
DOI: 10.1021/ci970015p     Document Type: Article

References (72)

1. Molchanova, M. S.; Shcherbukhin, V. V.; Zefirov, N. S. Computer Generation of Molecular Structures by the SMOG Program. J. Chem. Inf. Comput. Sci. 1996, 36, 888-899.
2. Lederberg, J.; Sutherland, G. L.; Buchanan, B. G.; Feigenbaum, E. A.; Robertson, A. V.; Duffield, A. M.; Djerassi, C. Applications of Artificial Intelligence for Chemical Inference. I. The Number of Possible Organic Compounds. Acyclic Structures Containing C, H, O, and N. J. Am. Chem. Soc. 1969, 91, 2973-2976.
3. (a) Masinter, M.; Sridharan, N. S.; Lederberg, J.; Smith, D. H. Applications of Artificial Intelligence for Chemical Inference. XII. Exhaustive Generation of Cyclic and Acyclic Isomers. J. Am. Chem. Soc. 1974, 96, 7702-7714.
4. (b) Carhart, R. E.; Smith, D. H.; Brown, H.; Djerassi, C. Applications of Artificial Intelligence for Chemical Inference. XVII. An Approach to Computer-Assisted Elucidation of Molecular Structure. J. Am. Chem. Soc. 1975, 97, 5755-5762.
5. (a) Smith, D. H.; Gray, N. A. B.; Nourse, J. G.; Crandell, C. W. The Dendral Project: Recent Advances in Computer-Assisted Structure Elucidation. Anal. Chim. Acta 1981, 133, 471-497.
6. (b) Carhart, R. E.; Smith, D. H.; Gray, N. A. B.; Nourse, J. G.; Djerassi, C. GENOA: A Computer Program for Structure Elucidation Utilizing Overlapping and Alternative Substructures. J. Org. Chem. 1981, 46, 1708-1718.
7. (c) Lindley, M.; Schoolery, J.; Smith, D.; Djerassi, C. Application of the Computer Program GENOA and Two-Dimensional NMR Spectroscopy to Structure Elucidation. Org. Magn. Reson. 1983, 21, 405-411.
8. Lindsay, R. K.; Buchanan, B. G.; Feigenbaum, E. A.; Lederberg, J. Applications of Artificial Intelligence for Organic Chemistry: The DENDRAL Project; McGraw-Hill: New York, 1980.
9. (a) Shelley, C. A.; Hays, T. R.; Roman, R. V.; Munk, M. E. An Approach to Automated Partial Structure Expansion. Anal. Chim. Acta 1978, 103, 121-132.
10. (b) Shelley, C. A.; Munk, M. E. CASE, a Computer Model of the Structure Elucidation Process. Anal. Chim. Acta 1981, 133, 507-516.
11. (c) Lipkus, A. H.; Munk, M. E. Automated Classification of Candidate Structures for Computer-Assisted Structure Elucidation. J. Chem. Inf. Comput. Sci. 1988, 28, 9-18.
12. Christie, B. D.; Munk, M. E. Structure Generation by Reduction: A New Strategy for Computer-Assisted Structure Elucidation. J. Chem. Inf. Comput. Sci. 1988, 28, 87-93.
13. Zhu, S.; Zhang, J. Exhaustive Generation of Structural Isomers for a Given Empirical Formula - A New Algorithm. J. Chem. Inf. Comput. Sci. 1982, 22, 34-38.
14. (a) Grund, R.; Kerber, A.; Laue, R. MOLGEN, a Computer Algebra System for Construction of Molecular Graphs. Commun. Math. Chem. (MATCH) 1992, 27, 87-131 (in German).
15. (b) Wieland, T.; Kerber, A.; Laue, R. Principles of the Generation of Constitutional and Configurational Isomers. J. Chem. Inf. Comput. Sci. 1996, 36, 413-419.
16. (c) Benecke, C.; Grund, R.; Hohberger, R.; Kerber, A.; Laue, R.; Wieland, T. MOLGEN+, a Generator of Connectivity Isomers and Stereoisomers for Molecular Structure Elucidation. Anal. Chim. Acta 1995, 314, 141-149.
17. (d) Benecke, C.; Grund, R.; Kerber, A.; Laue, R.; Wieland, T. Chemical Education via MOLGEN. J. Chem. Educ. 1995, 72, 403-406.
18. (e) Wieland, T. The Use of Structure Generators in Predictive Pharmacology and Toxicology. Arzneim.-Forsch. (Drug Res.) 1996, 46 (I), 223-227.
19. (a) Funatsu, K.; Miyabayashi, N.; Sasaki, S. Further Development of Structure Generation in the Automated Structure Elucidation System CHEMICS. J. Chem. Inf. Comput. Sci. 1988, 28, 18-28.
20. (b) Funatsu, K.; Susuta, J.; Sasaki, S. Introduction of Two-Dimensional NMR Spectral Information to an Automated Structure Elucidation System CHEMICS: Utilization of 2D-INADEQUATE Information. J. Chem. Inf. Comput. Sci. 1989, 29, 6-11.
21. (c) Funatsu, K.; Sasaki, S. Recent Advances in the Automated Structure Elucidation System CHEMICS. Utilization of Two-Dimensional NMR Spectral Information and Development of Peripheral Functions for Examination of Candidates. J. Chem. Inf. Comput. Sci. 1996, 36, 190-205.
22. Bauer, J.; Fontain, E.; Ugi, I. IGOR and RAIN-the First Mathematically Based Multipurpose Problem-Solving Computer Programs for Chemistry and Their Use as Generators of Constitutional Formulas. Commun. Math. Chem. (MATCH) 1992, 27, 31-47.
23. (a) Bohanec, S.; Zupan, J. Structure Generator GEN. Commun. Math. Chem. (MATCH) 1992, 27, 49-85.
24. (b) Bohanec, S. Structure Generation by the Combination of Structure Reduction and Structure Assembly. J. Chem. Inf. Comput. Sci. 1995, 35, 494-503.
25. (a) Molodtsov, S. G.; Piottukh-Peletsky, V. N. Generation of All Nonisomorphic Chemical Graphs from a Given Set of Structural Fragments. In Algorithms for the Analysis of Structural Information; Vychislitel'nye Sistemy: Novosibirsk, Russia, 1984; Vol. 103, pp 51-58 (in Russian).
26. (b) Molodtsov, S. G. Computer-Aided Generation of Molecular Graphs. Commun. Math. Chem. (MATCH) 1994, 30, 213-224.
27. (c) Molodtsov, S. G. Generation of Molecular Graphs with a Given Set of Nonoverlapping Fragments. Commun. Math. Chem. (MATCH) 1994, 30, 203-212.
28. Luinge, H. J. AEGIS, A Structure Generation Program in Prolog. Commun. Math. Chem. (MATCH) 1992, 27, 175-189.
29. Contreras, M.; Valdivia, R.; Rozas, R. Exhaustive Generation of Organic Isomers. (a) 1. Acyclic Structures. J. Chem. Inf. Comput. Sci. 1992, 32, 223-230. (b) 2. Cyclic Structures: New Compact Molecular Code. J. Chem. Inf. Comput. Sci. 1992, 32, 481-491. (c) 3. Acyclic, Cyclic, and Mixed Compounds. J. Chem. Inf. Comput. Sci. 1994, 34, 610-616.
30. Contreras, M.; Valdivia, R.; Rozas, R. Exhaustive Generation of Organic Isomers. (a) 1. Acyclic Structures. J. Chem. Inf. Comput. Sci. 1992, 32, 223-230. (b) 2. Cyclic Structures: New Compact Molecular Code. J. Chem. Inf. Comput. Sci. 1992, 32, 481-491. (c) 3. Acyclic, Cyclic, and Mixed Compounds. J. Chem. Inf. Comput. Sci. 1994, 34, 610-616.
31. Contreras, M.; Valdivia, R.; Rozas, R. Exhaustive Generation of Organic Isomers. (a) 1. Acyclic Structures. J. Chem. Inf. Comput. Sci. 1992, 32, 223-230. (b) 2. Cyclic Structures: New Compact Molecular Code. J. Chem. Inf. Comput. Sci. 1992, 32, 481-491. (c) 3. Acyclic, Cyclic, and Mixed Compounds. J. Chem. Inf. Comput. Sci. 1994, 34, 610-616.
32. Contreras, M.; Valdivia, R.; Rozas, R. Exhaustive Generation of Organic Isomers. (a) 1. Acyclic Structures. J. Chem. Inf. Comput. Sci. 1992, 32, 223-230. (b) 2. Cyclic Structures: New Compact Molecular Code. J. Chem. Inf. Comput. Sci. 1992, 32, 481-491. (c) 3. Acyclic, Cyclic, and Mixed Compounds. J. Chem. Inf. Comput. Sci. 1994, 34, 610-616.
33. Hu, Ch.-L.; Xu, L. Principles for Structure Generation of Organic Isomers from Molecular Formula. Anal. Chim. Acta 1994, 298, 75-85.
34. Faulon, J.-L. On Using Graph-Equivalence Classes for Structure Elucidation of Large Molecules. J. Chem. Inf. Comput. Sci. 1992, 32, 338-348.
35. Faulon, J.-L. Stochastic Generator of Chemical Structure. (a) 1. Application to the Structure Elucidation of Large Molecules. J. Chem. Inf. Comput. Sci. 1994, 34, 1204-1218. (b) 2. Using Simulated Annealing to Search the Space of Constitutional Isomers. J. Chem. Inf. Comput. Sci. 1996, 36, 731-740.
36. Faulon, J.-L. Stochastic Generator of Chemical Structure. (a) 1. Application to the Structure Elucidation of Large Molecules. J. Chem. Inf. Comput. Sci. 1994, 34, 1204-1218. (b) 2. Using Simulated Annealing to Search the Space of Constitutional Isomers. J. Chem. Inf. Comput. Sci. 1996, 36, 731-740.
37. Faulon, J.-L. Stochastic Generator of Chemical Structure. (a) 1. Application to the Structure Elucidation of Large Molecules. J. Chem. Inf. Comput. Sci. 1994, 34, 1204-1218. (b) 2. Using Simulated Annealing to Search the Space of Constitutional Isomers. J. Chem. Inf. Comput. Sci. 1996, 36, 731-740.
38. Bangov, I. P. Computer-Assisted Structure Generation from a Gross Formula. (a) 3. Alleviation of the Combinatorial Problem. J. Chem. Inf. Comput. Sci. 1990, 30, 277-289. (b) 4. Fighting against Graph-Isomorphism Disease. Commun. Math. Chem. (MATCH) 1992, 27, 3-30. (c) 7. Graph Isomorphism: A Consequence of the Vertex Equivalence. J. Chem. Inf. Comput. Sci. 1994, 34, 318-324.
39. Bangov, I. P. Computer-Assisted Structure Generation from a Gross Formula. (a) 3. Alleviation of the Combinatorial Problem. J. Chem. Inf. Comput. Sci. 1990, 30, 277-289. (b) 4. Fighting against Graph-Isomorphism Disease. Commun. Math. Chem. (MATCH) 1992, 27, 3-30. (c) 7. Graph Isomorphism: A Consequence of the Vertex Equivalence. J. Chem. Inf. Comput. Sci. 1994, 34, 318-324.
40. Bangov, I. P. Computer-Assisted Structure Generation from a Gross Formula. (a) 3. Alleviation of the Combinatorial Problem. J. Chem. Inf. Comput. Sci. 1990, 30, 277-289. (b) 4. Fighting against Graph-Isomorphism Disease. Commun. Math. Chem. (MATCH) 1992, 27, 3-30. (c) 7. Graph Isomorphism: A Consequence of the Vertex Equivalence. J. Chem. Inf. Comput. Sci. 1994, 34, 318-324.
41. Bangov, I. P. Computer-Assisted Structure Generation from a Gross Formula. (a) 3. Alleviation of the Combinatorial Problem. J. Chem. Inf. Comput. Sci. 1990, 30, 277-289. (b) 4. Fighting against Graph-Isomorphism Disease. Commun. Math. Chem. (MATCH) 1992, 27, 3-30. (c) 7. Graph Isomorphism: A Consequence of the Vertex Equivalence. J. Chem. Inf. Comput. Sci. 1994, 34, 318-324.
42. Abe, H.; Yamasaki, T.; Fujiwara, I.; Sasaki, S. Computer-Aided Structure Elucidation Methods. Anal. Chim. Acta 1981, 133, 499-506.
43. Gray, N. A. B. Computer-Assisted Structure Elucidation; Wiley: New York, 1986.
44. In ref 13c, the term "GOODLIST" is used in the same sense as "core fragments" in this paper. In our terminology, however, the difference between GOODLIST and the set of core fragments is rather subtle but still notable. In fact, GOODLIST is the whole set of fragments that must be present in the target molecules. At the same time, some fragments from GOODLIST (not necessarily all of them; see ref 1) may be used as ready construction units during generation, and only these fragments are called core fragments. Another subtle difference from the terminology of ref 13c is described in note 37.
45. Pólya, G. Combinatorial Enumeration for Groups, Graphs, and Chemical Compounds. Acta Sci. Math. 1937, 145-254.
46. Randic, M. Recognition of Identical Graphs Representing Molecular Topology. J. Chem. Phys. 1974, 60, 3920-3928.
47. Randic, M. On Canonical Numbering of Atoms in a Molecule and Graph Isomorphism. J. Chem. Inf. Comput. Sci. 1977, 17, 171-180.
48. (a) Kvasnicka, V.; Pospichal, J. Canonical Indexing and Constructive Enumeration of Molecular Graphs. J. Chem. Inf. Comput. Sci. 1990, 30, 99-105.
49. (b) Kvasnicka, V.; Pospichal, J. An Improved Version of the Constructive Enumeration of Molecular Graphs with Prescribed Sequence of Valence States. Chemom. Intell. Lab. Syst. 1993, 18, 171-181.
50. Other fragments are used indirectly within CHEMICS and must be checked for their presence in the generated structures. Also, CHEMICS is generally known to be somewhat nonrigorous as to the exclusion of duplicates (for example, see refs 12a, 15c, etc.).
51. To extend the notion of the automorphism group for a set of free valences, we represent all of the free valences by imaginary bonds that connect the corresponding atom(s) of the fragment to some dummy atoms (bonds with an unspecified terminus in Figure 2). Thus, we obtain the "expanded" graph of the fragment. The automorphism group of this expanded graph is regarded as the automorphism group of the set of free valences.
52. We had no possibility to check if the approach of MOLGEN finally yields irredundant results for arbitrary sets of core fragments, because recent papers describing this software (refs 9b-e) do not contain the data sufficient for proving or refuting this assumption. It would be especially interesting to see how the situation associated with construction of additional copies of fragments during generation (Figure 2b) is handled.
53. (a) Faradjev, I. A. Constructive Enumeration of Combinatorial Objects. In Algorithmic Investigations in Combinatorics; Faradjev, I. A., Ed.; Nauka: Moscow, 1978; pp 3-11 (in Russian).
54. (b) Faradjev, I. A. Generation of Nonisomorphic Graphs with a Given Degree Sequence. In Algorithmic Investigations in Combinatorics; Faradjev, I. A., Ed.; Nauka: Moscow, 1978; pp 11-19 (in Russian).
55. (c) Zaichenko, V. A.; Ivanov, A. B.; Rosenfeld, M. Z.; Faradjev, I. A. Algorithm of Canonicity Verification for a Partially Filled Adjacency Matrix of a Graph. In Algorithmic Investigations in Combinatorics; Faradjev, I. A., Ed.; Nauka: Moscow, 1978; pp 19-25 (in Russian).
56. 26b However, we will not consider this program in the present paper, because it is not aimed at direct use of arbitrary multiatomic fragments.
57. Harary, F. Graph Theory; Addison-Wesley: Reading, MA, 1969.
58. 1 However, to avoid unnecessary complications, hereafter we refer to such univalent atoms simply as hydrogens.
59. Hendrickson, J. B.; Toczko, A. G. Unique Numbering and Cataloguing of Molecular Structures. J. Chem. Inf. Comput. Sci. 1983, 23, 171-177.
60. Structural generation is aimed at producing connected molecular graphs, which correspond to covalently bound molecules. Methods for testing whether any full complement of a partially filled matrix may correspond to a connected structure (i.e., whether a partially assembled structure contains any disconnected parts without free valences) are known and simple, so we will not dwell further on this problem.
61. Rosenfeld, M. Z. Construction and Properties of Some Classes of Strongly Regular Graphs. Usp. Mat. Nauk 1973, 28, 197-198 (in Russian).
62. The term used in ref 13c is "pieces of stability" rather than "sets of stability". We changed this term in order to stress that these sets may be represented not only by single ranges ("pieces") but also by several disjoint ranges in our case.
63. 30c
64. Nechepurenko, M. I.; Popkov, V. K.; Mainagashev, S. M.; Kaul', S. B.; Proskuryakov, V. A.; Kokhov, V. A.; Gryzunov, A. B. Algorithms and Programs for the Solution of Problems on Graphs and Networks; Nauka: Novosibirsk, 1990; pp 123-157 (in Russian).
65. 12b proposed a comparison of algorithms with respect to their formal computational complexity; however, they also admitted that a lack of literature data and a strong dependence of the computational complexity on the actual problem under consideration make such a comparison impossible, at least presently.
66. Aromatic rings, such as benzene or pyridine, are regarded in this paper as formally consisting of alternating single and double bonds (rather than "aromatic" bonds of some intermediate multiplicity), because the same approach is used by the majority of existing generators, including GENM. That is, single and double bonds in aromatic rings are viewed as topologically nonequivalent. In general, SMOG can also handle them as equivalent, according to the user's desire, as is described in ref 1; in this case, the numbers of structures in some examples of Table 1 are additionally reduced.
67. As a result, if small (for example, two-atom) fragments are included in GOODLIST, sometimes it may be even preferable to assemble structures from separate atoms and check molecular graphs for the presence of these fragments during assembly (the straightforward approach mentioned in section 1.2!) rather than use these fragments directly as construction units. For larger fragments (≥3 atoms), however, the latter approach becomes incomparably more efficient.
68. i.
69. Ichibara, A.; Shiraishi, K.; Sato, H.; Sakamura, S.; Nishiyama, K.; Sakai, R.; Furusaki, A.; Matsumoto, T. The Structure of Coronatine. J. Am. Chem. Soc. 1977, 99, 636-637.
70. Munk, M. E.; Sodano, C. S.; McLean, R. L.; Haskell, T. H. Actinobolin: I. Structure of Actinobolamine. J. Am. Chem. Soc. 1967, 89, 4158-4165.
71. Ugi, I.; Wischhöfer, E. Isonitrile XI: Synthesis of a Simple Derivative of Penicillic Acid. Chem. Ber. 1962, 95, 136-140.
72. The distribution archive of SMOG (the MS-DOS version) may be obtained via FTP (either ftp://org.chem.msu.su/pub/chemistry/software/ SMOG or ftp://ccl.osc.edu/pub/chemistry/software/MS-DOS/SMOG). Using the first of these URLs, you may also obtain the "lite" version of the program, which was actually used for calculations cited in this paper. Any suggestions concerning possible improvement of the program functionality or removal of bugs will be accepted with gratitude. Please mail them to mary@lexa.ru.