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Target prediction, QSAR and conformal prediction


https://jcheminf.biomedcentral.com/articles/10.1186/s13321-018-0325-4 

You know that in the ChEMBL group, we love to play with the data we collect!! Back in April 2014, we started to work on a target prediction tool.  Wow! This was almost 5 years ago! Since then, we have continued to update the tool for each new ChEMBL release, providing you with the actual models and the result of the prediction on the ChEMBL website for the drug molecules. The good news is that these target predictions are not dead and a successor is on its way!

First, we would like to introduce you some closely related work. You may have heard about conformal prediction (CP). If not, it is a machine learning framework developed to associate confidence to predictions. I personally consider this as a requirement for decision making. Basically, you train a model as you would do in QSAR but then you first predict a so-called calibration set, for which you know the actual values. For each of these observations you obtain two probabilities: one for the active and one for the inactive class (in a typical classification scheme). Now that you have this information, each time you predict a new compound you compare its probabilities to those of the calibration set (the non-conformity scores as they are called) and you derived p-values for each class. Based on your predefined significance level, the compound can be assigned in different categories: only active or only inactive, but also both active and inactive or none of them. I am sure you can start seeing here the added value of CP!

Here I have briefly detailed how it works for classification models but CP can also be applied to regression models. If you want to know more about conformal prediction, I recommend you to read this book and also this very nice example of the application in drug discovery. Having learnt how to build conformal predictors, we were intrigued to know how well they perform against traditional QSAR models with our ChEMBL data!

With this in mind, we decided to build a panel of models using a substantial data set from ChEMBL. With our new protocol, we were able to build models for 788 targets (550 of them human targets). For the descriptors we used RDKit Morgan fingerprint (2048 bits and radius 2) and 6 physicochemical descriptors. For the machine learning part we used the good old Random Forests as implemented in Scikit-learn version 0.19. For the QSAR models, this is all that is needed, but for CP you need a framework and this was provided by the very nice library provided by Henrik Linusson.

The next part consisted of training the models and checking their internal performance, but we went a bit further and decided that with our models trained on ChEMBL_23 data, it would be interesting to see how they perform with new data in ChEMBL_24 in a so-called temporal validation. All the details, results and conclusion are presented in the recently accepted article!
Image result for right wrong decision

The dataset for each target is already available here and you can find the models ready to use there.

Feel free to take a look and to share your opinion in the comments.

Now, you remember that I started this post mentioning our good old target predictors. So does it mean a new generation of ChEMBL models using conformal prediction is ready to be launched for our users? Well, unfortunately not yet, but stay tuned!

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