Introduction to Chemoinformatics Irene Kouskoumvekaki Associate Professor December 12th, 2012 Biological Sequence Analysis course

2CBS, Department of Systems Biology Drug Discovery Process Disease Drug target Drug candidate Animal studies Clinical studies Marketed drug

3CBS, 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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5 Wet-lab drug discovery process Screening collection HTS Actives 10 3 actives10 6 cmp.

6CBS, Department of Systems Biology Screening collection HTS Actives 10 3 actives10 6 cmp. High rate of false actives!!! High throughput is not enough to get high output….. Wet-lab drug discovery process

7CBS, Department of Systems Biology Screening collection HTS Actives 10 3 actives10 6 cmp. Follow-up Chemical structure Purity Mechanism Activity value Wet-lab drug discovery process

8CBS, Department of Systems Biology Screening collection HTS Actives 10 3 actives10 6 cmp. Follow-up Hits 1-10 hits Analogues synthesis and testing ADMET properties Wet-lab drug discovery process

9CBS, Department of Systems Biology Wet-lab drug discovery process Screening collection HTS Actives 10 3 actives10 6 cmp. Follow-up Hits 1-10 hits Lead series 0-3 lead series Hit-to-lead Analogues synthesis and testing ADMET properties

10CBS, Department of Systems Biology Wet-lab drug discovery process Screening collection HTS Actives 10 3 actives10 6 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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12CBS, Department of Systems Biology Failures

13CBS, Department of Systems Biology We need more.. to find less..

14CBS, Department of Systems Biology Drug Discovery Process Disease Drug target Drug candidate Animal studies Clinical studies Marketed drug Chemoinformatics

15CBS, 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,...

16CBS, 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.)

17CBS, Department of Systems Biology Exercise : Prediction of drug-likeness Go to the following webpage Draw proguanil and decide if it is a drug- like compound

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19CBS, Department of Systems Biology Proguanil antimalarian tablets

20CBS, 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. dataprediction

21CBS, 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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23CBS, 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 C 8 H 9 NO 3

24CBS, 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

25CBS, 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

26CBS, 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

27CBS, 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

28CBS, 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

29CBS, 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

30CBS, Department of Systems Biology From chemists to representations

31CBS, Department of Systems Biology Structural representation of molecules Line notations Connection tables

32CBS, 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

33CBS, Department of Systems Biology InChI (IUPAC International Chemical Identifier)

34CBS, Department of Systems Biology MOLfile format (.sdf)

35CBS, Department of Systems Biology Small molecule databases

36CBS, 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

37CBS, Department of Systems Biology Try it yourself! Scroll down and find the SMILES and InChI

38CBS, Department of Systems Biology Try it yourself! Click on SDF (top right icon) Select: 2D SDF: Display

39CBS, Department of Systems Biology Try it yourself! Go back and click again on SDF Select: 3D SDF: Display

40CBS, Department of Systems Biology Questions?