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Irene Kouskoumvekaki, [email protected] Computational Chemical Biology, CBS May 14, 2009

Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

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Page 1: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Irene Kouskoumvekaki, [email protected] Chemical Biology, CBSMay 14, 2009

Page 2: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Oprea et al. Nature Chem Biol (2007) 3, 447-450

SMALL COMPOUNDSStructural informationBi ti it i f ti

HUMAN BODYBiological pathways

Bioactivity information Protein-protein interactionsGene expression dataDisease phenotypesDisease phenotypesSide effect data,etc... etc...

Page 3: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

WHY?d l ti it t d i l t t i ft• drug selectivity toward a single target is more often an

exception than the rule

• many effective drugs act via modulation of multiple targets

• many adverse drug reactions are due to activity towards other than the intented (primary) target

• some drugs may have yet unknown therapeutic targets (drug repurposing)repurposing)

•Integration of chemical and biological data can provide a g g ppicture of the network pharmacology of drugs

Page 4: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Chemogenomics profilingChemogenomics profiling

7,0

7,5

8,0

6,0

6,5

,0

pIC

50

5,0

5,5

m k d OR

L1

A3

a1 D1

D2

D3

D4

D5

H2

M1

M2

5-HT1

5-HT2

5-HT3

5-HT5

5-HT6

5-HT71 1A 2A 3 5A 6 7

Receptor List

Page 5: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Chemogenomics profilingC e oge o cs p o g

7,0

7,5

8,0

6,0

6,5

,0

pIC

50

5,0

5,5

m k d OR

L1

A3

a1 D1

D2

D3

D4

D5

H2

M1

M2

5-HT1

5-HT2

5-HT3

5-HT5

5-HT6

5-HT71 1A 2A 3 5A 6 7

Receptor List

Page 6: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Enzymes

TargetsNHR Ion Channels ProteasesGPCRKinases

unds

Com

pou

C

However we cannot synthesise and test everythingHowever... we cannot synthesise and test everything

Page 7: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

IC50 = 0.07 μM50 μ

Page 8: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

1A1

1A2

1B1

1B2

1B3

1C1

1C2

1C3

1H1

1H2

1H3

1H4

1I1

1I2

2B1

2B2

2B3

3A1

3A2

3B1

3B3

3C1

3C2

3C3

3C4

1A1

1A2

1B1

1B2

1B3

1C1

1C2

1C3

1H1

1H2

1H3

1H4

1I1

1I2

2B1

2B2

2B3

3A1

3A2

3B1

3B3

3C1

3C2

3C3

3C4

mpo

unds

ated

com

33an

nota

203

Mestres, et al. J. Chem. Inf. Model. 2006, 46, 2725-2736

Page 9: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Yildirim et al. Nature Biotechnology. 2007, 25, 1119-1126

Page 10: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

RationaleThe similar property principle states thatThe similar property principle states that structurally similar molecules tend to have similar propertiessimilar properties.

Query Annotated LibraryQuery Annotated Library

Page 11: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

RationaleThe similar property principle states thatThe similar property principle states that structurally similar molecules tend to have similar propertiessimilar properties.

Query Annotated LibraryQuery Annotated Library

Page 12: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Similarity Assessment

Molecule B

0 10 1

Molecule A 0 d b

1 a c

Tanimoto coefficient:T = c / (a+b+c)

Page 13: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Choosing the right descriptors can b diffi ltbe difficult...

Wolfgang Sauer, SMI 2004

Page 14: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Descriptors1D descriptors:

MW, number of ffeatures,…

fingerprints2D descriptors:

Topological, p gphysichochemical,

BCUT,…

2D/3D pharmacophores

Page 15: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

PharmacophorepA pharmacophore is the ensemble of steric and electronicp pfeatures that are necessary to ensure the optimal supramolecularinteractions with a specific biological target structure and totrigger (or to block) its biological response A pharmacophoretrigger (or to block) its biological response. A pharmacophoredoes not represent a real molecule or a real association offunctional groups, but a purely abstract concept that accountsf th l l i t ti iti f ffor the common molecular interaction capacities of a group ofcompounds towards their target structure.

Page 16: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Chemical pharmacophoric featuresThe chemical features can be hydrogen bonds

acceptors, hydrogen bond donors, charge interactions, hydrophobic areas, aromatic rings, positive or

negative ionizable groups. Distance, shape and volume can be also consideredvolume can be also considered.

HydAcc

Acc Aro

Acc & Don

Page 17: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

The chemist’s point of view

Aspirin SildenafilAspirin Sildenafil

Page 18: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Th i ’ i f iThe protein’s point of view

Aspirin SildenafilAspirin Sildenafil

Electrostatic fields (red: negative, blue: positive)

Page 19: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Oprea et al. Nature Chem Biol (2007) 3, 447-450

SMALL COMPOUNDSStructural informationBi ti it i f ti

HUMAN BODYBiological pathways

Bioactivity information Protein-protein interactionsGene expression dataDisease phenotypesDisease phenotypesSide effect data,etc... etc...

Page 20: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Oprea et al. Nature Chem Biol (2007) 3, 447-450

Page 21: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

L b t l S i (2006) 313 1929 1935Lamb et al. Science (2006) 313, 1929-1935

Page 22: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)
Page 23: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)
Page 24: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)
Page 25: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

http://www.cbs.dtu.dk/services/PGx_pipeline-1.0/

Page 26: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)
Page 27: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Questions?Q

Page 28: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Exercise

Page 29: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

ExercisePart 1• Go to: http://stitch.embl.de/Part 1

• Follow the mini-tutorial

• Interpret the output with the help of the article:

Kuhn et al., STITCH: interaction networks of h i l d i N l i A id R (2008)chemicals and proteins Nucleic Acids Res. (2008)

36, 684-688

Page 30: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Part 2Try searching STITCH with the human thymidylate

th (TYMS) t i i tsynthase (TYMS) protein as input.

The res lting net ork incl des se eral smallThe resulting network includes several small molecules.

Page 31: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

• Can you identify the product of thymidylateCan you identify the product of thymidylate synthase among them?

• Is the substrate of thymidylate synthase also present in the network?present in the network?

• Are these drugs structurally similar to eachAre these drugs structurally similar to each other?

• Are they similar to substrate of thymidylate synthase?synthase?

Page 32: Kouskoumvekaki, Chemical Biology, CBS · 2009. 5. 12. · Computational Chemical Biology, CBS May 14, 2009. Oprea et al. Nature Chem Biol (2007) 3, 447-450 ... ( drug repurposing)

Thymidine is required for DNA replication and repair to take place and inhibition of thymidinerepair to take place, and inhibition of thymidine synthase is thus harmful to proliferating cells. Indeed most of the small molecules in theIndeed, most of the small molecules in the network are drugs used for chemotherapy.