Introduction to Chemoinformatics and Drug Discovery Irene Kouskoumvekaki Associate Professor February 15 th, 2013 2CBS, Department of Systems Biology The Chemical Space There are atoms and space. Everything else is opinion. Democritus (ca. 460 BC ca. 370 BC) 3CBS, Department of Systems Biology Systems Chemical Biology 4CBS, Department of Systems Biology Todays Learning Objectives To introduce you to the field of chemoinformatics and the most commonly used terms and methods To show examples of the use of chemoinformatics in modern drug research To give you practical experience through hands-on exercises 5CBS, Department of Systems Biology Drug Discovery Process Disease Drug target Drug candidate Animal studies Clinical studies Marketed drug 6CBS, Department of Systems Biology A 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 proteins 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...) 7CBS, Department of Systems Biology 8 Wet-lab drug discovery process Screening collection HTS Actives 10 3 actives10 6 cmp. 9CBS, 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 10CBS, 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 11CBS, 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 12CBS, 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 13CBS, 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 14CBS, Department of Systems Biology 15CBS, Department of Systems Biology Failures 16CBS, Department of Systems Biology We need more.. to find less.. 17CBS, Department of Systems Biology Drug Discovery Process Disease Drug target Drug candidate Animal studies Clinical studies Marketed drug Chemoinformatics 18CBS, 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,... 19CBS, Department of Systems Biology The Lipinski rule of five for drug- likeness prediction Octanol-water partition coefficient (logP) 5 Molecular weight 500 # hydrogen bond acceptors (HBA) 10 # hydrogen bond donors (HBD) 5 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.) 20CBS, Department of Systems Biology Exercise : Drug-likeness by rule of five Go to the following webpageDraw proguanil, calculate properties and decide if this compound is a drug according to rule of five 21CBS, Department of Systems Biology 22CBS, Department of Systems Biology Proguanil antimalarian tablets 23CBS, 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 24CBS, 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 25CBS, 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 26CBS, Department of Systems Biology 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 C 8 H 9 NO 3 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 (aromatic ring identification) stereochemical configuration charges isotopes 3D-coordinates for atoms 30CBS, 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 31CBS, 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 32CBS, 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 33CBS, 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 34CBS, Department of Systems Biology From chemists to representations 35CBS, Department of Systems Biology Structural representation of molecules Line notations Connection tables 36CBS, 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 37CBS, Department of Systems Biology InChI (IUPAC International Chemical Identifier) 38CBS, Department of Systems Biology MOLfile format (.sdf) 39CBS, Department of Systems Biology Small molecule databases 40CBS, 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 41CBS, Department of Systems Biology Try it yourself! Scroll down and find the SMILES and InChI 42CBS, Department of Systems Biology Try it yourself! Click on SDF (top right icon) Select: 2D SDF: Display 43CBS, Department of Systems Biology Try it yourself! Go back and click again on SDF Select: 3D SDF: Display 44CBS, Department of Systems Biology Questions? 45CBS, Department of Systems Biology