Build a Weight of Evidence for Drug Candidate Molecules
by Roman Affentranger, Douglas Connect, Switzerland
Summary
Prerequisites
For this exercise, you need Java installed. If you are not sure whether you have Java installed or not, you can check here: http://java.com/en/download/installed.jsp.
To download and install Java, go to http://java.com.
Introduction
In 2010, the Tres Cantos Medicines Development Campus of GlaxoSmithKline deposited a collection of compounds – the Tres Cantos Antimalarial Compound Set, TCAMS – at the ChEMBL Neglected Tropical Disease Database (https://www.ebi.ac.uk/chemblntd) making the data publicly available. Each of the 13533 chemicals in the TCAMS inhibits growth of the 3D7 strain of Plasmodium falciparum – the malaria causing parasite – by at least 80% at a concentration of 2 µM. 5267 compounds in TCAMS also show the same effect against the multi-drug resistant P. falciparum strain DD2. Evidence for liver toxicity is provided by growth inhibition data against human hepatoma HepG2 cells. Over the whole TCAMS, 3137 compounds inhibit HepG2 growth by 40% or more at a concentration of 10 µM.
In this tutorial we will work on a subset of 87 compounds of the TCAMS, and we will use several OpenTox in combination to help prioritize these molecules for further investigation as drug candidates. The subset of 87 TCAMS compounds can be downloaded here. The file contains the identifiers of the compounds, as used in TCAMS, along with their SMILES and the cytotoxicity data of each compound against two P. falciparum strains (3D7 and DD2) and against human hepatoma HepG2 cells. Cytotoxicity is given as percentage growth inhibition at a compound concentration of 2 µM in the case of the two P. falciparum strains and at a concentration of 10 µM in the case of HepG2 cells.
P. falciparum 3D7 is one of the strains responsible for many infections in particular in children. P. falciparum DD2 is a multi-drug resistand strain of Plasmodium. The cytotoxicity data against HepG2 serves as an in vitro marker for general liver toxicity. We will add toxicity predictions to complement the toxicity information.
Start the tutorial with step 1. Creation of an OpenTox dataset from a local file