1. Structure Generation,
Metabolite Space, and
Metabolite-Likeness
Julio E. Peironcely  @peyron
Juliopeironcely.com
PhD student at Leiden University and TNO

2. Metabolomics
the quantitative and qualitative
analysis of all metabolites in
samples of cells, body fluids,
tissues, etc.
Julio E. Peironcely

3. Metabolomics
Experi- Biological
Biological Sample Data Data pre- Data
mental Sampling inter-
question preparation acquisition processing analysis
design pretation
Metabolites
Relevant
biomolecules/
List of
Samples Raw data connectivities
Protocol peaks/
&
biomolecules
Models
Julio E. Peironcely

4. Metabolomics
Experi- Biological
Biological Sample Data Data pre- Data
mental Sampling inter-
question preparation acquisition processing analysis
design pretation
Metabolites
Relevant
biomolecules/
List of
Samples Raw data connectivities
Protocol peaks/
&
biomolecules
Models
Julio E. Peironcely

5. De-novo identification

6. We have
Elemental Composition
Fragments (sometimes)
Experimental Information
Julio E. Peironcely

7. We want
List Of Candidate Structures
As Short As Possible
Good Structure Is In The List
Julio E. Peironcely

8. We need
Structure Generator
Keep only metabolites
Use experimental information to
filter molecules
Julio E. Peironcely

9. Elemental
Composition
Julio E. Peironcely

10. Elemental
Composition
Structure
Generation
Julio E. Peironcely

11. Elemental
Composition
Structure
Generation
Molecules
Julio E. Peironcely

12. Structure Generator
Elemental
Fragments
Formula
Generate
Candidate
Structures
In collaboration with Jean-Loup Faulon, Evry University
Julio E. Peironcely

13. Structure Generator
Elemental
Fragments
Formula
Generate
Keep
Molecules
if
Canonical
Augmenta:on
Candidate
Structures
In collaboration with Jean-Loup Faulon, Evry University
Julio E. Peironcely

14. Structure Generator Adding bonds
In collaboration with Jean-Loup Faulon, Evry University
Julio E. Peironcely

15. Structure Generator Isomorphism
Isomorphic class Isomorphic class
“triangle + 1 edge” “3-edge chain”
1 1 1 1
1 2 3 2 3 1
2 3 2 3
1 3 1 2 3
4 2 4 4
4 1
3 2 3 4
2 4
3 2 3
4 2 4
4 4
In collaboration with Jean-Loup Faulon, Evry University
Julio E. Peironcely

16. Structure Generator Isomorphism
Isomorphic class Isomorphic class
“triangle + 1 edge” “3-edge chain”
1 1 1 1
1 2 3 2 3 1
2 3 2 3
1 3 1 2 3
4 2 4 4
4 1
3 2 3 4
2 4
3 2 3
4 2 4
4 4
Output
ONLY
orange
graphs
In collaboration with Jean-Loup Faulon, Evry University
Julio E. Peironcely

17. Structure Generator Canonical Labeling
1 1 1 1
1 2 3 2 3 1
2 3 2 3
1 3 1 2 3
4 2 4 4
4 1
3 2 3 4
2 4
3 2 3
4 2 4
4 4
Canonizer
(Nauty)
(1,2) (1,3) (1,4) (1,2) (1,3) (2,4)
(2,3)
Julio E. Peironcely

18. Only 1 canonical
labeling in each
isomorphic class

19. Use canonizer to 1
remove duplicates after 2 3
5
4
each extension 1 (1,2)
2 3
4 5
1 1
(1,2)(1,3)
2 3 2 3
4 5 4 5
(1,2)(1,3)(1,4) (1,2)(1,3)
(2,3)
1 1 1 1
2 2 3 2 3 2 3 1
3
5 5 4 5 5
4 4 4 2 3
(1,2)(1,3)(1,4) (1,2)(1,3)(1,4) (1,2)(1,3)(1,4)
(2,3) 4 5
(3,4) (4,5)
(1,2)(1,3)
X
(2,3)(2,4)

20. Canonical Augmentation
A canonical object
augmented in a canonical way
produces a canonical object
Julio E. Peironcely

21. Check For Canonical Augmentation
Keep object if
a canonical deletion
takes you to the canonical father
Julio E. Peironcely

22. Accept only canonically 1
2 3
augmented graphs 4
(1,2)
5
1
2 3
4 5
1 1
(1,2)(1,3)
2 3 2 3
4 5 4 5
(1,2)(1,3)(1,4) (1,2)(1,3)
(2,3)
1 1 1 1
2 2 3 2 3 2 3 1
3
5 5 4 5 5
4 4 4 2 3
(1,2)(1,3)(1,4) (1,2)(1,3)(1,4) (1,2)(1,3)(1,4)
(2,3) 4 5
(3,4) (4,5)
(1,2)(1,3)
X
(2,3)(2,4)
X

23. Structure Generator Results MOLGEN
same # of
molecules
p-Cresol
Glycine Phenylalanine Malic acid D-Cysteine
sulfate
Elemental
C2H5NO2 C9H11NO2 C4H6O5 C3H7NO2S C7H8O3S
Composition
# Output
84 277,810,163 8,070 3,838 10,203,389
Molecules
6 4,037,499 1,601 100 19,940
1 Fragment
93,137 948
2 Fragments 584
3 Fragments 278
In collaboration with Jean-Loup Faulon, Evry University
Julio E. Peironcely

24. Lots of candidates
structures

25. We are looking for
metabolites

26. Elemental
Composition
Structure Metabolite
Generation Likeness
Molecules
Julio E. Peironcely

27. Elemental
Composition
Metabolites
Structure Metabolite
Generation Likeness
Molecules
Julio E. Peironcely

28. How do metabolites
look like?
Understanding and Classifying Metabolite Space and Metabolite-Likeness
Julio E. Peironcely et al. PLoS One (in press)

29. HMDB ZINC
8K 21M
Julio E. Peironcely

30. metabolites non metabolites
Water Solubility
MW
C Atoms
Struc. Complexity
PSA
Julio E. Peironcely

31. PCA
Julio E. Peironcely

32. PCA

33. Not so different

34. Decision Tree
Julio E. Peironcely

35. Elemental
Composition
Metabolites
Structure Metabolite
Generation Likeness
Molecules
Julio E. Peironcely

36. Metabolite-likeness
Representation + Classification
HMDB ZINC
8K 21M
Atom Counts
Physicochemical desc. Support Vector
Machines (SVM)
MDL Public Keys
Random Forest (RF)
FCFP_4
Naïve Bayes (NB)
ECFP_4
Julio E. Peironcely

37. Metabolite-likeness HMDB
8K
ZINC
21M
Standardization
Atom Counts Diversity Selection
Physicochemical desc.
MDL Public Keys
FCFP_4
ECFP_4
Julio E. Peironcely

38. Metabolite-likeness HMDB
8K
ZINC
21M
Standardization
Atom Counts Diversity Selection
Physicochemical desc.
MDL Public Keys
FCFP_4 Training Set Test Set
ECFP_4 532 + 532 6.4K + 6.4K
Julio E. Peironcely

39. Metabolite-likeness HMDB
8K
ZINC
21M
Standardization
Atom Counts Diversity Selection
Physicochemical desc.
MDL Public Keys
FCFP_4 Training Set Test Set
ECFP_4 532 + 532 6.4K + 6.4K
5-fold CV
SVM RF BC
Julio E. Peironcely

40. Metabolite-likeness HMDB
8K
ZINC
21M
Standardization
Diversity Selection
3 classifiers
X
Training Set Test Set
5 descriptions 532 + 532 6.4K + 6.4K
5-fold CV Metabolite
likeness
SVM RF BC
Julio E. Peironcely

41. Metabolite-likeness HMDB
8K
ZINC
21M
Best = RF – MDLPublicKeys Standardization
Sensitivity Specificity AUC
Diversity Selection
99.84% 87.52% 99.20%
Training Set Test Set
Bad BC – P_desc 532 + 532 6.4K + 6.4K
Sensitivity Specificity AUC 5-fold CV Metabolite
likeness
SVM RF BC
42.51% 86.56% 61.57%
Julio E. Peironcely

42. Metabolite-likeness, external
validation
HMDB
External DrugBank ChEMBL
validation set
Random Selection
Standardization
Metabolite
likeness
Julio E. Peironcely

43. Metabolite-likeness, external
validation
Julio E. Peironcely

45. Met-likeness + structure generation
(malic acid) 8K
100%
57% 77%
Julio E. Peironcely

46. Met-likeness + structure generation
(methylhistamine) 260K
71%
46%
Julio E. Peironcely

47. What else do we know
about our molecules?

48. Molecule Minimized_Energy ALogP Index
Phenylalanine 0.1100 -1.605 5142

49. Molecule Minimized_Energy ALogP Index
C9H11NO2
0.1100 -1.605 5142
Structure
Generation
277 M
Julio E. Peironcely

50. Molecule Minimized_Energy ALogP Index
C9H11NO2
0.1100 -1.605 5142
99%
Structure
Generation
44%
41 K
Julio E. Peironcely

51. Molecule Minimized_Energy ALogP Index
C9H11NO2
E < 10 0.1100 -1.605 5142
Structure
Generation
40%
8K
Julio E. Peironcely

52. Molecule Minimized_Energy ALogP Index
C9H11NO2
E < 10 0.1100 -1.605 5142
ALogP < -1
Structure
Generation
76%
31
Julio E. Peironcely

53. Conclusions
Met-Likeness prediction is good,
interpretation not
Local models needed
Structure Generator + Met-Likeness
+ other constraints = Met Id
improvement
Julio E. Peironcely

54. Acknowledgements
Leiden University University of Cambridge
Miguel Rojas-Cherto Andreas Bender
Piotr Kasper
Michael van Vliet
Theo Reijmers
Rob Vreeken Evry University
Ronnie van Doorn Jean-Loup Faulon
Thomas Hankemeier Davide Fichera
TNO Quality of Life
Leon Coulier
Albert Tas HMP University of
Alberta
David Wishart
Ying (Edison) Dong
Julio E. Peironcely