EcoDrug+: an advanced database for drug target conservation analysis and environmental risk assessment

90-Minute Technical Workshop Participant Handout

Case Study:CLOZAPINE

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Module 1

Chemical Selection & Human Target Profiling

Chemical and primary target information for Clozapine

Chemical information
Search by Name: Clozapine
Search by Identifier:
  • CAS RN: 5786-21-0
  • ChEMBL ID: CHEMBL42

      • Chemical Representation:
      • SMILES: CN1CCN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)CC1
Clozapine Target profile
Primary targets:
Dopamine D2 receptor
  • Gene Symbol: DRD2
  • Gene Name: dopamine receptor D2
  • Chromosomal Location:11q23.2
  • Ensembl Gene : ENSG00000149295
5-HT2A receptor
  • Gene Symbol: HTR2A
  • Gene Name: 5-hydroxytryptamine receptor 2A
  • Chromosomal Location:13q14.2
  • Ensembl Gene : ENSG00000102468
Module 2

Evolutionary Target Conservation & Orthology Mapping

Mapping human drug targets onto 180+ environmental wildlife species using Ensembl-derived phylogenetic comparisons, identifying species vulnerable to unintentional target-mediated toxicity.

Input data
  • Human target: DRD2 (Dopamine receptor D2) / HTR2A (5-hydroxytryptamine receptor 2A)
  • BLAST sequence : Calculates sequence identity matches to establish read-across the species
      • Example: Dopamine receptor D2 sequence
      >sp|P14416|DRD2_HUMAN D(2) dopamine receptor OS=Homo sapiens OX=9606 GN=DRD2 PE=1 SV=2
      MDPLNLSWYDDDLERQNWSRPFNGSDGKADRPHYNYYATLLTLLIAVIVFGNVLVCMAVS REKALQTTTNYLIVSLAVADLLVATLVMPWVVYLEVVGEWKFSRIHCDIFVTLDVMMCTA SILNLCAISIDRYTAVAMPMLYNTRYSSKRRVTVMISIVWVLSFTISCPLLFGLNNADQN ECIIANPAFVVYSSIVSFYVPFIVTLLVYIKIYIVLRRRRKRVNTKRSSRAFRAHLRAPL KGNCTHPEDMKLCTVIMKSNGSFPVNRRRVEAARRAQELEMEMLSSTSPPERTRYSPIPP SHHQLTLPDPSHHGLHSTPDSPAKPEKNGHAKDHPKIAKIFEIQTMPNGKTRTSLKTMSR RKLSQQKEKKATQMLAIVLGVFIICWLPFFITHILNIHCDCNIPPVLYSAFTWLGYVNSA VNPIIYTTFNIEFRKAFLKILHC
BLAST parameter
Scoring matrix: Default BLOSUM62.
Sensitivity mode
The default mode will run which is designed for finding hits of >60% identity and short read alignment.
  • fast: Enable the fast sensitivity mode, which runs faster than default and is designed for finding hits of >90% identity.
  • mid-sensitive Enable the mid-sensitive mode which is between the default mode and the sensitive mode in sensitivity.
  • sensitive:Enable the sensitive mode designed for full sensitivity for hits of >40% identity.
  • more-sensitive: This mode is equivalent to the --sensitive mode except for soft-masking of certain motifs being disabled (same as setting --motif-masking 0).
  • very-sensitive: Enable the very-sensitive mode designed for best sensitivity including the twilight zone range of <40% identity
  • ultra-sensitive: Enable the ultra-sensitive mode which is yet more sensitive than the very-sensitive mode
Sequence Identity (%)
  • Report only alignments above the given percentage of sequence identity
      • e-value
      • Maximum expected value to report an alignment (default=0.001).
      Query Coverage (%)
      • Report only alignments above the given percentage of query cover
Target conservation across-Species
High conservation in fish (e.g., Danio rerio matching >65% identity for neuroreceptors); low or absent matching in invertebrates.
Module 3

Chemical Similarity

Groups structurally related substances (~7.2k pharmaceuticals, 34k agrochemicals, 61k metabolites) into interactive knowldege graphs.

Input data
Search by Name: Clozapine
Search by Identifier:
  • CAS RN: 5786-21-0
  • ChEMBL ID: CHEMBL42

      • Chemical Representation:
      • SMILES: CN1CCN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)CC1
Parameter
  • Exact
  • Similarity (Tanimoto threshold >= cut off)
  • Substructure
Clozapine similar
Maps closely linked dibenzodiazepine derivatives (e.g., Olanzapine, Quetiapine) into active, common environmental hazard vectors.
Module 4

Environmental Exposure

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Integration
Cross-references Measured Environmental Concentrations (MECs) against localized wastewater streams.
Risk Analaysis
Module 5

REST API Endpoints

Fetches compound information, mechanism of action and target conservation across species using the EcoDrug+ preferred name

Compound Information
https://ecodrugplus.helsinki.fi/api/v1/data/Compounds/preferred_name/Clozapine
Mechanism of Action
https://ecodrugplus.helsinki.fi/api/v1/data/DrugMechanism/preffred_name/Clozapine
Target conservation across the species
All species
  • https://ecodrugplus.helsinki.fi/api/v1/data/TargetConservation/organism/Homo sapiens/preffred_name/Clozapine

Example organism: Zebra fish
  • https://ecodrugplus.helsinki.fi/api/v1/data/TargetConservation/organism/Homo%20sapiens/target_species/Danio%20rerio/preffred_name/Clozapine
EcoDrug+ developed in collaboration with the University of Helsinki and the University of Exeter.