introduction to chemoinformatics irene kouskoumvekaki associate professor december 12th, 2012...
TRANSCRIPT
![Page 1: Introduction to Chemoinformatics Irene Kouskoumvekaki Associate Professor December 12th, 2012 Biological Sequence Analysis course](https://reader036.vdocument.in/reader036/viewer/2022081504/56649e7c5503460f94b7df99/html5/thumbnails/1.jpg)
Introduction to Chemoinformatics
Irene KouskoumvekakiAssociate Professor
December 12th, 2012Biological Sequence Analysis course
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2 CBS, Department of Systems Biology
Drug Discovery Process
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3 CBS, Department of Systems Biology
The drug candidate
... is a (ligand) compound that binds to a biological target (protein, enzyme, receptor, ...) and in this way either initiates a process (agonist) or inhibits it (antagonist/inhibitor)
The structure/conformation of the ligand is complementary to the space defined by the protein’s active site
The binding is caused by favorable interactions between the ligand and the side chains of the amino acids in the active site. (electrostatic interactions, hydrogen bonds, hydrophobic contacts...)
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4 CBS, Department of Systems Biology
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5 CBS, Department of Systems Biology
Wet-lab drug discovery process
Screening collection
HTS
Actives
103 actives106 cmp.
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6 CBS, Department of Systems Biology
Screening collection
HTS
Actives
103 actives106 cmp.
High rate of false actives!!!
High throughput is not enough to get high output…..
Wet-lab drug discovery process
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7 CBS, Department of Systems Biology
Screening collection
HTS
Actives
103 actives106 cmp.
Follow-up Chemical structure
Purity
Mechanism
Activity value
Wet-lab drug discovery process
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8 CBS, Department of Systems Biology
Screening collection
HTS
Actives
103 actives106 cmp.
Follow-up
Hits
1-10 hits
Analogues synthesis and testing
ADMET properties
Wet-lab drug discovery process
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9 CBS, Department of Systems Biology
Wet-lab drug discovery process
Screening collection
HTS
Actives
103 actives106 cmp.
Follow-up
Hits
1-10 hits
Lead series
0-3 lead series
Hit-to-lead
Analogues synthesis and testing
ADMET properties
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10 CBS, Department of Systems Biology
Wet-lab drug discovery process
Screening collection
HTS
Actives
103 actives106 cmp.
Follow-up
Hits
1-10 hits
Lead series
0-3 lead series
Hit-to-lead
Drug candidate
0-1
Lead-to-drug
Analogues synthesis and testing
ADMET properties
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11 CBS, Department of Systems Biology
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12 CBS, Department of Systems Biology
Failures
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13 CBS, Department of Systems Biology
We need more.. to find less..
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14 CBS, Department of Systems Biology
Drug Discovery Process
Chemoinformatics
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15 CBS, Department of Systems Biology
Wet-lab + Dry-lab drug discovery
Diverse set of molecules tested in the lab
in vitro in silico + in vitro
Computational methods to select subsets (to be tested in the lab) based on prediction of drug-likeness, solubility, binding, pharmacokinetics, toxicity, side effects, ...
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16 CBS, Department of Systems Biology
The Lipinski ‘rule of five’ for drug-likeness prediction
Molecular weight ≤ 500 # hydrogen bond acceptors (HBA) ≤ 10 # hydrogen bond donors (HBD) ≤ 5 Octanol-water partition coefficient (logP) ≤ 5 (MlogP ≤ 4.15)
If two or more of these rules are violated, the compound might
have problems with oral bioavailability.(Lipinski et al., Adv. Drug Delivery Rev., 23, 1997, 3.)
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17 CBS, Department of Systems Biology
Exercise : Prediction of drug-likeness
•Go to the following webpagewww.molsoft.com/mprop
•Draw proguanil and decide if it is a drug-like compound
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18 CBS, Department of Systems Biology
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19 CBS, Department of Systems Biology
Proguanil antimalarian tablets
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20 CBS, Department of Systems Biology
Chemoinformatics
Gathering and systematic use of chemical information, and application of this information to predict the behavior of unknown compounds in silico.
data prediction
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21 CBS, Department of Systems Biology
Major Aspects of Chemoinformatics
•Databases: Development of databases for storage and retrieval of small molecule structures and their properties.
•Machine learning: Training of Decision Trees, Neural Networks, Self Organizing Maps, etc. on molecular data.
•Predictions: Molecular properties relevant to drugs, virtual screening of chemical libraries, system chemical biology networks…
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22 CBS, Department of Systems Biology
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23 CBS, Department of Systems Biology
Representing a chemical structure
• How much information do you want to include?– atoms present– connections between atoms
• bond types– stereochemical configuration– charges– isotopes – 3D-coordinates for atoms
C8H9NO3
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24 CBS, Department of Systems Biology
Representing a chemical structure
• How much information do you want to include?– atoms present– connections between atoms
• bond types– stereochemical configuration– charges– isotopes – 3D-coordinates for atoms
OH
CH2
CHNH2OH
O
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25 CBS, Department of Systems Biology
Representing a chemical structure
• How much information do you want to include?– atoms present– connections between atoms
• bond types (aromatic ring identification)
– stereochemical configuration– charges– isotopes – 3D-coordinates for atoms
OH
CH2
CHNH2OH
O
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26 CBS, Department of Systems Biology
Representing a chemical structure
• How much information do you want to include?– atoms present– connections between atoms
• bond types– stereochemical configuration– charges– isotopes – 3D-coordinates for atoms
OH
CH2
CHNH2OH
O
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27 CBS, Department of Systems Biology
Representing a chemical structure
• How much information do you want to include?– atoms present– connections between atoms
• bond types– stereochemical configuration– charges– isotopes– 3D-coordinates for atoms
OH
CH2
CHNH3+
O
O
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28 CBS, Department of Systems Biology
Representing a chemical structure
• How much information do you want to include?– atoms present– connections between atoms
• bond types– stereochemical configuration– charges– isotopes– 3D-coordinates for atoms
OH
CH2
C14 HNH2OH
O
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29 CBS, Department of Systems Biology
Representing a chemical structure
• How much information do you want to include?– atoms present– connections between atoms
• bond types– stereochemical configuration– charges– isotopes– 3D-coordinates for atoms
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30 CBS, Department of Systems Biology
From chemists to representations
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31 CBS, Department of Systems Biology
Structural representation of molecules
Structural representation of moleculesLine notations
Connection tables
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32 CBS, Department of Systems Biology
SMILES (Simplified Molecular Input Line Entry System)
Canonical SMILES: unique for each structure
Isomeric SMILES: describe isotopism, configuration around double bonds and tetrahedral centers, chirality
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33 CBS, Department of Systems Biology
InChI(IUPAC International Chemical Identifier)
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34 CBS, Department of Systems Biology
MOLfile format (.sdf)
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35 CBS, Department of Systems Biology
Small molecule databases
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36 CBS, Department of Systems Biology
Try it yourself!
• Go to PubChem: pubchem.ncbi.nlm.nih.gov/
• Type proguanil and press Go
• Click on the first result on the list
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37 CBS, Department of Systems Biology
Try it yourself!
• Scroll down and find the SMILES and InChI
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38 CBS, Department of Systems Biology
Try it yourself!
• Click on SDF (top right icon)
• Select: 2D SDF: Display
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39 CBS, Department of Systems Biology
Try it yourself!
• Go back and click again on SDF
• Select: 3D SDF: Display
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40 CBS, Department of Systems Biology
Questions?