ChemAxon's hERG Predictor

Version 1.0-beta-2

This documentation gives a short introduction to ChemAxon's hERG (hERG-beta) Predictor.

Table of Contents

• What is hERG?
• ChemAxon's hERG model
  • Data used for model building
  • Applicability domain
  • Accuracy report
• How to use the hERG Predictor?
  • MarvinSketch
  • Playground
  • Design Hub
  • cxcalc
  • Chemical Terms
  • Summary table
• Licensing
• References
• Release notes

What is hERG?

hERG potassium channels play an essential role in normal electrical activity of the heart, mediating the cardiac action potential of the heartbeat. Affecting their activity by xenobiotics can have life-threatening consequences. Accordingly, hERG is one of the most important off-targets of drug discovery.

Optimisation to reduce the risk of inhibiting the hERG channels during discovery projects requires computational prediction in the early design throughout the pre-synthesis phase. The hERG channel inhibition capacity of a drug is measured by its hERG activity (Act).

Experimentally, hERG activity is determined by different electrophysiological methods and measured as IC₅₀ or K_i values. However, as with other physico-chemical properties (e.g. pK_a), the negative logarithm of the measured activity (pAct) is used in the literature:

pAct = -log₁₀(Act)

ChemAxon's hERG model

Data used for model building

The model was built using multiple publicly available data sources, including the hERG Central DataBase, ChEMBL and various selected publications and patents. Our current hERG model encapsulates structure activity relationships (SARs) from around 2500 pAct data points.

Applicability domain

We used Random Forest and Conformal Prediction algorithms to create the model and to provide an applicability domain of hERG prediction. The applicability domain provides information about the model's performance and accuracy.

The applicability domain is based on the 5 most similar compounds from the training set according to ECFP-4 fingerprints and Tanimoto metrics. The error bound of the applicability domain comes from the Conformal Prediction algorithm.

NOTE: The hERG applicability domain is currently ONLY available in Playground and Design Hub.

Accuracy report

We ran a test to validate the predictive capabilities of the hERG model on a test set of around 270 molecules. The test resulted in a 0.80 Pearson correlation coefficient and a 0.55 RMSE. 72% of the test set molecules had delta distribution less than 0.5.

The accuracy report is available here.

How to use the hERG Predictor?

The hERG Predictor is able to predict hERG pActivity and is currently available in MarvinSketch, in the Playground and Design Hub web applications, in the cxcalc command line tool and the Chemical Terms language from v. 20.20.

MarvinSketch

In MarvinSketch predicting hERG activity can be done with the hERG (Beta) Plugin, which can be found under the Calculations » ADMET menu item.

Playground

You can predict hERG activity in Playground by selecting hERG under the Explore Calculations menu. Once selected, the predicted value with its applicability domain appears next to the drawing canvas.

Design Hub

In Design Hub predicting hERG activity can be done with the Add Property » hERG menu item. The predicted activity value with its applicability domain appears next to the drawing canvas.

cxcalc

To predict hERG activity with cxcalc, use the herg-beta function:

cxcalc herg-beta aspirine
4.16

Chemical Terms

To predict hERG activity with Chemical Terms, use the hergBeta() function:

evaluate -e "hergBeta()" aspirine
4.16

Summary table

The following table summarises the availability of the hERG prediction and applicability domain features in the above mentioned products.

Product name	hERG prediction	Applicability domain
MarvinSketch	✅	❌
Playground	✅	✅
Design Hub	✅	✅
Cxcalc	✅	❌
Chemical Terms	✅	❌

Licensing

To access and use the hERG Predictor you need a valid ChemAxon ADMET license. Please consult us for more information on licensing.

References

1. Du, Fang et al. (2011). hERGCentral: A large database to store, retrieve and analyse compound-human ether-à-go-go related gene channel interactions to facilitate cardiotoxicity assessment in drug development, Assay and Drug Development Technologies, 9(6), 580-588. https://doi.org/10.1089/adt.2011.0425
2. ChemBL 27, ChemBL database

Release notes

hERG v. 1.0-beta:

• Default ChemAxon hERG model (hERG-beta) is built and available for prediction
• hERG Predictor is released in MarvinSketch, cxcalc and Chemical Terms

hERG v. 1.0-beta-2:

• hERG prediction is available in Playground
• Applicability domain is implemented and available in Playground and Design Hub