Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Predict Toxicity from Structure

Larry H. Bernstein, MD, FCAP, Curator

LPBI

chemTox

http://www.cyprotex.com/insilico/physiological_modelling/chemtox

Toxicity Prediction Directly from Chemical Structure

• Predicts key toxicity parameters (Ames mutagenicity, rat acute dose LD₅₀ following iv or po administration) and aqueous solubility directly from structure.
• No in vitro physicochemical or toxicity data required.
• Save money and time by allowing toxicity to be assessed virtually (no synthesis required).
• Provides early stage filter for directing chemistry and prioritizing screening.

A virtual screening tool for predicting toxicity from chemical structure alone.

chemTox is implemented as a node for the KNIME analytics platform which executes a model of the workflow illustrated in Figure 1 below.

Figure 1
chemTox workflow.

Data from chemTox

Figure 2
Receiver operating characteristic (ROC) plots for classification of rat acute LD₅₀ following oral administration. (a) LD₅₀ < 5mg/kg (b). LD₅₀ < 50mg/kg (c). LD₅₀ < 300mg/kg.

(a).
LD₅₀ < 5mg/kg

(b).
LD₅₀ < 50mg/kg

(c).
LD₅₀ < 300mg/kg

SJ Williams

Tempting but there have been other databases like ToxNet which have used SAR (structure activity relationship) for Ames prediction but usually that is far as it can go. This is usually a first screen but long term carcinogenicity studies are still required for obvious reasons. In addition no system can predict IDILI (idiopathic drug induced liver injury) which has and still is plaguing the drug development industry. This is where relationships need to be worked on and this problem will need a more indepth ‘omic strategy as there are no SARs which correlate with these “idiosyncratic” toxicities. However be that as it may there have been chemicals which failed the Ames test however were not carcinogenic in subchronic or chronic tests so it is still good to conduct those studies anyway, even though most regulatory bodies give a failed Ames test a bad thumbs down.