Knowledge Fair Table B - Drug Discovery Application
An example of a predictive toxicology application in drug discovery is given using the data on antimalarial compounds made available at the ChEMBL Neglected Tropical Disease (NTD) archive (http://www.ebi.ac.uk/chemblntd/). The data was imported and made available via a specially installed OpenTox dataset service, to emulate a drug discovery exercise working in a setup separate from public dataset services. OpenTox model services are used for predicting toxicities.
For this workshop activity, we combined all three data sets from the ChEMBL NTD archive in a newly created OpenTox data service: the Tres Cantos Antimalarial TCAMS dataset (>13'000 antimalarials found in a 2-million compound screening library of GlaxoSmithKline), the Novartis-GNF dataset (>5'000 antimalarials) and the St. Jude Children's Research Hospital dataset (>1'100 antimalarials, 172 of which were studied in great detail). More information on these datasets can be found at http://www.ebi.ac.uk/chemblntd/.
Workshop Activity:
A) Prioritizing the Antimalarials
Step 1
The antimalarial compounds are prioritized based on a very conservative model for predicting oral toxicity. More specifically, Cramer rules (a model for predicting oral toxicity) are applied to all datasets. Cramer rules is a very conservative model, that is, if it predicts a chemical to be save (class I), there is high probability it will be safe indeed. Food ingredients, for example, are classified as Class I.
Step 2
Experimentally determined cytotoxicities against human cells of the compounds predicted to be safe (Cramer class I) are further examined, and their mutagenicities predicted via Toxtree Benigni Bossa rules.
Step 3
A new dataset is created with compounds that have no mutagenicity alerts, low human cytotoxicity, but high anti-malarial activity. Potential sites of cytochrome P450 metabolism are predicted for for this dataset.
Download detailed instructions for this activity here...
B) Additional exercise:
Extract subsets of data to be used to create a model via the OpenTox demo application ToxCreate.
Download detailed instructions for this activity here...
