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Small Molecules in Bioinformatics

Small Molecules in Bioinformatics. EBI Bioinformatics Roadshow 16th March 2011 Dusseldorf. Agenda. Introduction Small molecule resources ChEMBL ChEBI Searching and browsing Hands-on Exercises. Annotation of bioinformatics data.

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Small Molecules in Bioinformatics

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  1. Small Molecules in Bioinformatics EBI Bioinformatics Roadshow16th March 2011Dusseldorf

  2. Agenda Introduction Small molecule resources ChEMBL ChEBI Searching and browsing Hands-on Exercises Small molecule resources at the EBI

  3. Annotation of bioinformatics data Essential for capturing and understanding and knowledge associated with core data Often captured in free text, which is easier to read and better for conveying understanding to a human audience, but… • Difficult for computers to parse • Quality varies from database to database • Terminology used varies from annotator to annotator • Towards annotation using standard vocabularies: ontologies within bioinformatics Small molecule resources at the EBI

  4. Small molecules participate in all processes of life

  5. What are Small Molecules? A small molecule is defined as a low molecular weight organic compound. Most drugs are small molecules to allow passage over cell membranes and oral bioavailability. They are also able to bind to proteins and enzymes, thereby altering function, which can lead to a therapeutic effect. Small molecules are used in everyday life.

  6. Some common small molecules: Amino Acids

  7. γ-aminobutyric acid Signaling • GABA: chief inhibitory neurotransmitter in the mammalian central nervous system. • In humans, also regulates muscle tone. • synthesized by neurons • found mostly as a zwitterion, that is, with the carboxyl group deprotonated and the amino group protonated • conformational flexibility of GABA is important for its biological function, as it has been found to bind to different receptors with different conformations • GABA deficiency linked to • anxiety disorder, depression, alcoholism • multiple sclerosis, action tremors, tardive dyskinesia Small molecule resources at the EBI

  8. Adenosine 5'-triphosphate Metabolism Adenosine 5’-triphosphate (ATP): the "molecular unit of currency" of intracellular energy transfer. • generated in the cell by energy-consuming processes, broken down by energy-releasing processes • proteins that bind ATP do so in a characteristic protein fold known as the Rossmann fold, which is a general nucleotide-binding structural domain that can also bind the cofactor NAD Small molecule resources at the EBI

  9. Enzymes • Enzyme inhibitors are molecules that bind to enzymes and decrease their activity. • Many drugs are enzyme inhibitors. They are also used as herbicides and pesticides. • Enzyme activators bind to enzymes and increase their enzymatic activity. • Enzyme activators are often involved in the allosteric regulation of enzymes in the control of metabolism. clavulanic acid acts as a suicide inhibitor of bacterial β-lactamase enzymes Small molecule resources at the EBI

  10. Pathways http://www.genome.jp/kegg-bin/highlight_pathway?scale=1.0&map=map00231&keyword=tryptophan Small molecule resources at the EBI

  11. Systems biology BioModels: quantitative models of biochemical and cellular systems tryptophan D-enantiomer: sweet L-enantiomer: bitter Small molecule resources at the EBI

  12. Drug types 2003 - 2009 'Small molecules' in various shades of blue (http://chembl.blogspot.com/) Small molecule resources at the EBI

  13. Small Molecule Databases • Small Molecule Databases can be used to: • Investigate historical compounds and associated bioactivity data. • To give fresh insight into previously rejected drugs. • Create Structure-Activity Relationships (SARs) • Look at how changing a functional group can change the biological activity of a compound – before you start your own synthesis. Small molecule resources at the EBI

  14. Direct synthesis • Could reduce number of compounds made – if any similar compounds have significant toxicity or unfavourable binding data, you can save time by not making analogues. • Direct end product testing • Suggest what testing could be carried out – the database can give you an idea of what testing has given ‘good’ (i.e. clear) results. • Reduce number of compounds put through High Throughput Screening (HTS). Small molecule resources at the EBI

  15. ChEBI and ChEMBL Small molecule resources at the EBI

  16. What is ChEBI? Chemical Entities of Biological Interest Freely available Focused on ‘small’ chemical entities (no proteins or nucleic acids) Illustrated dictionary of chemical nomenclature High quality, manually annotated Provides chemical ontology Access ChEBI at http://www.ebi.ac.uk/chebi/ Small molecule resources at the EBI

  17. ChEBI home page Small molecule resources at the EBI

  18. ChEBI data overview Nomenclature Ontology metaboliteCNS stimulanttrimethylxanthines caffeine1,3,7-trimethylxanthine methyltheobromine Chemical data Database Xrefs Formula: C8H10N4O2Charge: 0 Mass: 194.19 MSDchem: CFFKEGG DRUG: D00528 Chemical Informatics Visualisation InChI=1/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3 SMILES: CN1C(=O)N(C)c2ncn(C)c2C1=O

  19. ChEBI entry view ChEBI – Chemical Entities of Biological Interest

  20. Chemical Structures Chemical structure may be interactively exploredusing MarvinView applet Available in formats Image Molfile InChI and InChIKey SMILES Small molecule resources at the EBI

  21. Automatic Cross-references ChEBI – Chemical Entities of Biological Interest

  22. What is ChEMBL? Database of bioactive, drug-like small molecules. Contains 2D structures, calculated properties (logP, mol weight, Lipinski etc) Contains abstracted bioactivity data, e.g. binding data and IC50, from multiple primary scientific journals Covers about 30 years of compound synthesis and testing Annotated FDA-approved drugs Access ChEMBL at https://www.ebi.ac.uk/chembldb/ Small molecule resources at the EBI

  23. ChEMBL Main Search Page Small molecule resources at the EBI

  24. Clickable structure Drug Information Calc. properties Master headline Small molecule resources at the EBI

  25. Structural Representations Small molecule resources at the EBI

  26. Small molecule resources at the EBI

  27. Parent and Salt Forms Database links Small molecule resources at the EBI

  28. ChEBI Link: Small molecule resources at the EBI

  29. This will take you back to ChEMBL

  30. ChemSpider Links: The link works both ways. They link TO ChemSpider and FROM ChemSpider. They link on Standard_Inchi Small molecule resources at the EBI

  31. Wikipedia Links: We also have links with Wikipedia. These also use the Standard_Inchi as the common identifier. These links will link to the Compound Report Card in ChEMBL. The links are added by a ChemoBot and can be updated with each release, if required. Small molecule resources at the EBI

  32. STRUCTURAL REPRESENTATION Small molecule resources at the EBI

  33. Stereoisomers Compounds that have same molecular formula and configuration, but differ in the 3-dimensional orientations. The central tetrahedral carbon has 4 different molecular groups/atoms attached. This is known as the chiral centre. Small molecule resources at the EBI

  34. Stereoisomerism Example - Thalidomide Caused thousands of deformities in babies across 46 countries between 1957 and 1961. The R isomer is to control morning sickness but the S isomer was teratogenic. Sparked more tightly controlled laboratory practices across the world. Small molecule resources at the EBI

  35. Stereoisomers Where known, the stereochemistry of the compound is noted in the structure and in the name. If a stereoisomer of an existing compound is submitted, it is given a separate id number. If a mixture of two stereoisomers had data submitted, we will also give this a separate id number if the activity of the compounds can not be isolated. If you draw a planar compound into the structure search, you will receive data on all stereoisomers. Small molecule resources at the EBI

  36. Ofloxacin, Levofloxacin and Dextrofloxacin • Fluoroquinolone antibiotics • Ofloxacin is a racemic (equal) mixture of Levo and Dextro isomers. • Levofloxacin is the more active stereoisomer • Dextrofloxacin is the less active stereoisomer • ChEMBL has data on each with separate bioactivities. Small molecule resources at the EBI

  37. Tautomers (keto-enol form) • Two forms readily interconvert via the migration of a hydrogen to the adjacent oxygen and the swapping of a single to a double bond, and vice versa. • ChEMBL does not differentiate between different tautomers. • The preferred tautomeric structure is retained. • ChEBI does differentiate and will store the separate tautomers. Small molecule resources at the EBI

  38. Salts • About 50% of marketed drugs are combined with salts to aid in their activity. • Some salts prevent the drug from being absorbed in the mouth. • Some salts help the drug be activated in the intestines, rather than the stomach. • There are approx 40,200 ChEMBL compounds with salts. • Bioactivity data is recorded against the parent drug and against the salt. • Therefore, it’s important to give these compounds different ChEMBL ids. Small molecule resources at the EBI

  39. Salt Example: Morphine • Morphine can be adminstered with many different salts: • Hydrochloride (HCl) • Sulphate (SO4) • Tartrate • Acetate • Citrate • Methobromide (MeBr) • Hyrobromide (HBr) • Hydroiodide (HI) • Lactate • Chloride (Cl) • Bitartrate Small molecule resources at the EBI

  40. Dealing with Salts in ChEMBL Each compound, if in a salt form, is analysed and matched to a ‘parent’ – i.e. the base form of the compound. (Not inorganic compounds) For example, morphine hydrochloride (CHEMBL556578), morphine sulfate (CHEMBL422878) and morphine sulfate hydrate (CHEMBL1200603) are matched to their parent morphine (CHEMBL70) This relationship is shown on the interface of the compound page. Additionally, when you run a search for a compound, you will only be brought back the parent form in the results grid. Small molecule resources at the EBI

  41. Parents and Salts on the Compound Page SALTS (with hyperlinks beneath) PARENT (compound report page) Small molecule resources at the EBI

  42. Morphine - All Data Morphine HCl specific data Clicking on the Bioactivity Summary pie chart will give you the bioactivity data for ALL forms of the compound To get salt specific bioactivity data, click on the hyperlink beneath the salt form of interest to be taken to its compound page. Small molecule resources at the EBI

  43. Naming and Classification Small molecule resources at the EBI

  44. Chemical names Common or trivial names are those that are highly used. Advantages of common names include simplicity, pronounceability and universally recognised The main disadvantage is ambiguity – the same common name may refer to more than one type of chemical. Small molecule resources at the EBI

  45. Systematic names A systematic name is one which corresponds to the chemical structure such that the structure can be determined from the name, e.g. 1,2-dimethyl-naphthalene Software packages exist which can generate structures from the systematic names (e.g. ACD/Name, ChemOffice, MarvinSketch). More than one correct systematic name can be assigned to the same molecular structure, depending on the manner in which naming rules are applied. Small molecule resources at the EBI

  46. Examples of common and systematic names Common names Systematic names 1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione 7-methyltheophylline 1,3,7-trimethyl-2,6-dioxopurine caffeineguaraninetheine Small molecule resources at the EBI

  47. SEARCHING IN CHEBI

  48. Why? • Ontological data • Structure classification • Chemical entity, e.g. hydrocarbon • Role, e.g. ligand • Subatomic particle, e.g. electron • Links to other databases • Kegg • DrugBank • PDBEChem • Citations

  49. How? Text-based Drawing

  50. The ChEBI ontology Organised into three sub-ontologies, namely Molecular structure ontology Subatomic particle ontology Role ontology (R)-adrenaline Small molecule resources at the EBI

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