How to Approach Machine Learning-based Prediction ofDrug/Compound-Target Interactions

The identification of drug/compound-target interactions (DTIs) constitutes the basis of drug discovery, for which computational predictive approaches have been applied. As a relatively new data-driven paradigm, proteochemometric (PCM) modeling utilizes both protein and compound properties as a pair at the input level and processes them via statistical/machine learning. The representation of input samples (i.e., proteins and their ligands) in the form of quantitative feature vectors is crucial for the extraction of interaction-related properties during the artificial learning and subsequent prediction of DTIs. Lately, the representation learning approach, in which input samples are automatically featurized via training and applying a machine/deep learning model, has been utilized in biomedical sciences. In this study, they performed a comprehensive investigation of different computational approaches/techniques for protein featurization (including both conventional approaches and the novel learned embeddings), data preparation and exploration, machine learning-based modeling, and performance evaluation with the aim of achieving better data representations and more successful learning in DTI prediction. For this, they first constructed realistic and challenging benchmark datasets on small, medium, and large scales to be used as reliable gold standards for specific DTI modeling tasks. They developed and applied a network analysis-based splitting strategy to divide datasets into structurally different training and test folds. Using these datasets together with various featurization methods, they trained and tested DTI prediction models and evaluated their performance from different angles. Their main findings can be summarized under 3 items: (i) random splitting of datasets into train and test folds leads to near-complete data memorization and produce highly over-optimistic results, as a result, it should be avoided, (ii) learned protein sequence embeddings work well in DTI prediction and offer high potential, even though no information related to protein structures, interactions or biochemical properties is utilized during their generation, and (iii) PCM models tend to learn from compound features and leave out protein features, mostly due to the natural bias in DTI data, indicating the requirement for new and unbiased datasets. They hope this study will aid researchers in designing robust and high performing data-driven DTI prediction systems that have real-world translational value in drug discovery.

(i) They proposed challenging benchmark datasets with high coverage on both compound and protein spaces that can be used as reliable, reference/gold-standard datasets for DTI modelling tasks. These datasets are protein family-specific, and each has three versions in terms of train/test splits for different prediction tasks (i.e., random split for predicting known inhibitors for known targets, dissimilar-compound split for predicting novel inhibitors for known targets, and fully-dissimilar split for predicting new inhibitors for new targets). Thus, they yield fair evaluation of models at multiple difficulty levels and facilitate the prevention of over-optimistic performance results. They evaluated these datasets in the framework of PCM modeling, which is a highly promising data-driven approach for high performance ML-based drug discovery. These datasets can be used in future studies to evaluate newly proposed modeling and/or algorithmic techniques for DTI prediction.

(ii) They employed a network-based strategy for splitting data into train-test folds, by considering both protein-protein and compound-compound pairwise similarities, which is proposed here for the first time, according to their knowledge. This strategy ensures that train and test folds are totally dissimilar from each other, with a minimum loss of data points. One of the current limitations in drug development is the problems related to discovering novel molecules that are structurally different from existing drugs and drug candidates. The network-based splitting strategy they applied here forces prediction models to face this limitation by supplying more realistic, hard-to-predict test samples. Hence, it can aid researchers in designing more powerful and robust DTI prediction models that have a real translational value.

(iii) Protein representation learnings a wide range of applications with promising results in different sub-fields of protein science, despite being a relatively new approach. However, the studies regarding their usage in DTI prediction modeling are limited, and there is no comprehensive benchmark study to evaluate their performance against well-known and widely used featurization approaches. Due to this reason, they extended the scope of their study by involving state-of-the-art learned representations and discussing their potential in DTI prediction.