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Irene Kouskoumvekaki, [email protected] 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.