kouskoumvekaki, chemical biology, cbs · 2009. 5. 12. · computational chemical biology, cbs may...

Irene Kouskoumvekaki, irene@cbs.dtu.dkComputational Chemical Biology, CBSMay 14, 2009

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...

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

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

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

Enzymes

TargetsNHR Ion Channels ProteasesGPCRKinases

unds

Com

pou

C

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

IC50 = 0.07 μM50 μ

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

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

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

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

Similarity Assessment

Molecule B

0 10 1

Molecule A 0 d b

1 a c

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

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

Wolfgang Sauer, SMI 2004

Descriptors1D descriptors:

MW, number of ffeatures,…

fingerprints2D descriptors:

Topological, p gphysichochemical,

BCUT,…

2D/3D pharmacophores

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.

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

The chemist’s point of view

Aspirin SildenafilAspirin Sildenafil

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

Aspirin SildenafilAspirin Sildenafil

Electrostatic fields (red: negative, blue: positive)

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...

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

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

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

Questions?Q

Exercise

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

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.

• 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?

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.