George  Papadatos,  PhD  Senior  Technical  Officer  ChEMBL  group  georgep@ebi.ac.uk  

Leveraging  public  domain  bioactivity  data  with  KNIME  

Genomes Ensembl

Ensembl Genomes EGA

Nucleotide sequence ENA

Functional genomics

ArrayExpress Expression Atlas

Protein Sequences UniProt

Protein families, motifs and domains

InterPro

Macromolecular PDBe

Protein activity IntAct, PRIDE

Pathways Reactome

Systems BioModels

BioSamples

Literature and ontologies CiteXplore, GO

Chemogenomics ChEMBL

•  ChEMBL database •  Curation •  Interface •  Research group

Chemical entities ChEBI

EMBL-­‐EBI  structure  

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Outline  •  Overview  of  ChEMBL  database  

•  IntroducGon,  contents,  access  •  What  ChEMBL  do  with  KNIME  •  What  KNIME  can  do  with  ChEMBL  

•  ChEMBL  KNIME  nodes  •  OpenChEMBL  •  UniChem  

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The  ChEMBL  Database  

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What  is  ChEMBL?  •  Open  access  database  for  drug  discovery  •  Freely  available  –  searchable  and  downloadable  •  Contents:  

•  BioacGvity  data  manually  extracted  from  the  primary  medicinal  chemistry  literature  

•  Deposited  data  from  neglected  disease  screening  (e.g.  Malaria)  •  Subset  of  data  from  PubChem  

•  BioacGvity  data  is  associated  with  a  biological  target  and  a  chemical  structure    

•  Updated  regularly  with  new  data  

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Drug  discovery  process  

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Target Discovery

Lead Discovery

Lead Optimisation

Preclinical Development

Phase I Phase II Phase III Launch

• Target identification • Microarray profiling • Target validation • Assay development • Biochemistry • Clinical/Animal disease models

• High-throughput Screening (HTS) • Fragment-based screening • Focused libraries • Screening collection

• Medicinal Chemistry • Structure-based drug design • Selectivity screens • ADMET screens • Cellular/Animal disease models • Pharmacokinetics

• Toxicology • In vivo safety pharmacology • Formulation • Dose prediction

PK Tolerability

Efficacy Safety & Efficacy

Indication Discovery & expansion

Medicinal chemistry SAR Clinical candidates Drugs

Discovery Development Use

Clinical trials

KNIME  UGM  

>1,200,000  disGnct  compounds  ~27,000  disGnct  lead  series  

~12,000  candidates    

~1,400  drugs  

ChEMBL  database  

What  is  in  ChEMBL?  

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SAR Data

Compound

Ass

ay

Ki = 4.5 nM

>Thrombin MAHVRGLQLPGCLALAALCSLVHSQHVFLAPQQARSLLQRVRRANTFLEEVRKGNLERECVEETCSYEEAFEALESSTATDVFWAKYTACETARTPRDKLAACLEGNCAEGLGTNYRGHVNITRSGIECQLWRSRYPHKPEINSTTHPGADLQENFCRNPDSSTTGPWCYTTDPTVRRQECSIPVCGQDQVTVAMTPRSEGSSVNLSPPLEQCVPDRGQQYQGRLAVTTHGLPCLAWASAQAKALSKHQDFNSAVQLVENFCRNPDGDEEGVWCYVAGKPGDFGYCDLNYCEEAVEEETGDGLDEDSDRAIEGRTATSEYQTFFNPRTFGSGEADCGLRPLFEKKSLEDKTERELLESYIDGRIVEGSDAEIGMSPWQVMLFRKSPQELLCGASLISDRWVLTAAHCLLYPPWDKNFTENDLLVRIGKHSRTRYERNIEKISMLEKIYIHPRYNWRENLDRDIALMKLKKPVAFSDYIHPVCLPDRETAASLLQAGYKGRVTGWGNLKETWTANVGKGQPSVLQVVNLPIVERPVCKDSTRIRITDNMFCAGYKPDEGKRGDACEGDSGGPFVMKSPFNNRWYQMGIVSWGEGCDRDGKYGFYTHVFRLKKWIQKVIDQFGE

APTT = 11 min Targets  

Compounds  

BioacFviFes  

N

N

N

N

N

ON

O

N

O

H

H

H

H

H

PublicaFon  

What  is  in  ChEMBL?  

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ChEMBL_15  Compounds:  1,254,575    Assays:  679,259  Targets:  9,570  PublicaGons:  48,735  AcGviGes:  10,509,572  Data  sources:  16  

Increase  of  >230,000  compounds  from  literature  since  ChEMBL01  

How  to  access  ChEMBL?  1.  Web  interface  •  IntuiGve  and  secure  •  Compound,  assay,  target  search  

2.  SQL  dumps  and  flat  files  •  Oracle,  MySQL,  Postgresql*  dumps  and  .sd  file  

3.  RESTful  web  services  •  Exact,  substructure  &  similarity  search  •  BioacGviGes  for  compound,  assay  and  target  id  

•  hdps://www.ebi.ac.uk/chembldb/index.php/ws  

•  KNIME  examples  

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How  KNIME  is  used  in  the  group    •  I/O,  file  conversions,  data  retrieval  and  manipulaGon  

•  e.g.  format  Open  Source  Drug  Discovery  malaria  data  deposiGons  

•  ChemoinformaGcs,  data  modelling  and  visualisaGon  •  Ligand-­‐based  target  fishing  •  Data  quality  assurance  •  Automated  data  curaGon  

•  Text  mining  •  Chemical  named-­‐enGty  recogniGon  •  Document  classificaGon  

•  ChEMBL-­‐likeness  

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ChEMBL  KNIME  Nodes  

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RESTful  Web  Services  for  KNIME  •  Compound,  assay  and  target  look-­‐up  

•  CHEMBL_ID  (or  UniProt  Accession  for  targets)  as  input  

•  BioacGviGes  for  compound,  assay  and  target  •  CHEMBL_ID  as  input  

•  Compound  searching  •  Molecular  structure  as  input  •  Exact,  similarity  and  substructure  searching  

•  Advantages  •  Tighter  integraGon  of  KNIME  and  ChEMBL  data  •  No  need  for  internal  ChEMBL  database  or  SQL  queries  •  No  need  for  a  chemical  cartridge  

 hdps://www.ebi.ac.uk/chembldb/index.php/ws  

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ChEMBL  KNIME  nodes  

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hdp://tech.knime.org/book/embl-­‐ebi-­‐nodes  

Example:  All  bioactivities  for  hERG  

All  bioacGviGes  for  hERG  

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AcGvity  value,  assay  descripGon,  compound,  reference  

Example:  Compound  searching  in  ChEMBL  

Query  

List  of  NNs  

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Example:  Polypharmacology  proMile  

Compounds

Query  

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Find  NNs  

Retrieve  bioacGviGes    

Filter,  summarise  &  pivot    

…what  next?  •  Chemical  space  clustering  &  visualisaGon  •  (Q)SAR  analysis  

•  Data  modeling,  acGvity  cliffs,  FW,  MMP  analysis  •  Bioisosteric  replacements  mining  

•  De  novo  design  •  EvoluGonary  compound  opGmisaGon  

•  Target  fishing  •  (off-­‐)target  predicGon  and  ADR  analysis  •  Polypharmacology  networks  •  Druggability  /  Drug-­‐likeness  

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Download  the  ChEMBL  KNIME  workMlows    

…via  the  KNIME  Example  Flow  Server:  

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OpenChEMBL  +  KNIME  

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OpenChEMBL  Virtual  Machine  •  Packaged  in  a  VM  

•  ChEMBL  db,  Postgresql,  RDKit  toolkit  and  cartridge  •  Ubuntu  12.04  •  Exported  as  OVF  

•  Can  be  imported  by  VirtualBox  etc.  

•  Provides  •  Direct  database  connecGon  •  Custom  web  interface  •  Web  services  for  structure  search  

•  Available  as  lp  download  soon  

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OpenChEMBL  Interface  

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Using  KNIME  to  connect  to  the  VM  

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SELECT mr.*, md.chembl_id, cp.full_mwt, cp.alogp from mols_rdkit mr, molecule_dictionary md, compound_properties cp

where mr.m @> '$${SMolecule}$$'::qmol and mr.molregno = md.molregno and md.molregno = cp.molregno;

UniChem  +  KNIME  

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UniChem:  Linking  to  other  sources  

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 All  EBI  DBs  share  the  benefits  of  maintained  links  to  internal  and  external  resources  

etc.  EU_OPENSCREEN  

 The  ‘mapping  service’  will  be  opened  for  use  by  external  users  hdp://www.jcheminf.com/content/5/1/3/abstract  

KNIME  +  UniChem  

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ChEMBL  resources  

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ChEMBL  blog:  hdp://chembl.blogspot.com  

If  you  would  like  help:  chembl-­‐help@ebi.ac.uk  

For  ChEMBL  news  and  data  releases:  hdp://listserver.ebi.ac.uk/mailman/lisGnfo/chembl-­‐announce  

Webinars  

hdp://www.slideshare.net/gpapadatos/knime-­‐tutorial  

Summary  •  KNIME:  democraGzing  access  to  data  and  tools  •  Accessing  public  domain  structure  and  bioacGvity  data  with  KNIME  •  ChEMBL  KNIME  Nodes  •  OpenChEMBL  +  KNIME  •  UniChem  +  KNIME  

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Acknowledgements  •  ChEMBL  group  

•  Edmund  Duesbury  •  Rodrigo  Ochoa  •  Jon  Chambers  •  Mark  Davies  •  Shaun  McGlinchey  •  Anna  Gaulton  •  John  Overington  

•  Stephan  Beisken  

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•  RDKit  •  KNIME  •  KNIME  community  •  All  of  you  for  listening  

George  Papadatos,  PhD  Senior  Technical  Officer  ChEMBL  group  georgep@ebi.ac.uk  

Leveraging  public  domain  bioactivity  data  with  KNIME