In-silico target prediction by ensemble chemogenomic model based on multi-scale information of chemical structures and protein sequences

Abstract

Identification and validation of bioactive small-molecule targets is a significant challenge in drug discovery. In recent years, various in-silico approaches have been proposed to expedite time- and resource-consuming experiments for target detection. Herein, we developed several chemogenomic models for target prediction based on multi-scale information of chemical structures and protein sequences. By combining the information of a compound with multiple protein targets together and putting these compound-target pairs into a well-established model, the scores to indicate whether there are interactions between compounds and targets can be derived, and thus a target prediction task can be completed by sorting the outputted scores. To improve the prediction performance, we constructed several chemogenomic models using multi-scale information of chemical structures and protein sequences, and the ensemble model with the best performance was used as our final model. The model was validated by various strategies and external datasets and the promising target prediction capability of the model, i.e., the fraction of known targets identified in the top-k (1 to 10) list of the potential target candidates suggested by the model, was confirmed. Compared with multiple state-of-art target prediction methods, our model showed equivalent or better predictive ability in terms of the top-k predictions. It is expected that our method can be utilized as a powerful computational tool to narrow down the potential targets for experimental testing.

Keywords: Chemogenomic; Ensemble model; Target prediction; XGBoost.

Fig. 1

Category distribution of 859 targets for prediction

Fig. 2

The distribution of the numbers of the positive samples and negative samples associated with each target

Fig. 3

ROC curves of models derived from different descriptors (integrated or separated groups) on the stratified tenfold CV

Fig. 4

ROC curves of three ensemble models on the stratified tenfold CV

Fig. 5

The recall rates of six individual models and our model within various top k values (k = 1–10) measured on the stratified 10-CV