SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules

Abstract

SwissTargetPrediction is a web tool, on-line since 2014, that aims to predict the most probable protein targets of small molecules. Predictions are based on the similarity principle, through reverse screening. Here, we describe the 2019 version, which represents a major update in terms of underlying data, backend and web interface. The bioactivity data were updated, the model retrained and similarity thresholds redefined. In the new version, the predictions are performed by searching for similar molecules, in 2D and 3D, within a larger collection of 376 342 compounds known to be experimentally active on an extended set of 3068 macromolecular targets. An efficient backend implementation allows to speed up the process that returns results for a druglike molecule on human proteins in 15-20 s. The refreshed web interface enhances user experience with new features for easy input and improved analysis. Interoperability capacity enables straightforward submission of any input or output molecule to other on-line computer-aided drug design tools, developed by the SIB Swiss Institute of Bioinformatics. High levels of predictive performance were maintained despite more extended biological and chemical spaces to be explored, e.g. achieving at least one correct human target in the top 15 predictions for >70% of external compounds. The new SwissTargetPrediction is available free of charge (www.swisstargetprediction.ch).

Figure 1.

SwissTargetPrediction input page. Major novelties and updated items are boxed in blue. These include the upper black banner that provides links to other in-house CADD online tools, including new ones. Links to the old version of SwissTargetPrediction, FAQ, help and download pages are provided in the header's menu. After having selected the species, the query molecule is inputted either as SMILES or by using the MarvinJS sketcher for opening, importing or modifying a molecular structure. A ‘Clear’ button allows deleting all inputs, and examples can be selected from a drop-down menu. The ‘Predict targets’ button becomes red and active when an input molecule is given.

Figure 2.

Prediction output page. Major novelties and updated items are boxed in blue. Upper-left: recall of the query molecule structure (here: a pyrrolopyrazine JAK inhibitor from patent US2014155376A1, not included in ChEMBL23) and interoperability icons to submit the compound to SwissADME, SwissSimilarity or SwissTargetPrediction for further analysis, or to get the query SMILES. Below, other icons allow downloading the results as PDF, CSV or Excel files, as well as printing or copying them to the clipboard. Upper-right: the summary of the predicted target classes is displayed as a pie chart, whose percentages are calculated using the top 15, 25, 50 or all predicted targets (maximum 100). The main table lists the predicted most probable targets for the query molecule. By default, proteins are ranked according to their probability of being the actual target (depicted has green bars), but the dynamic table can be sorted by any column by clicking on the corresponding header. By default, the number of displayed rows is 15, but the user can choose 25, 50 or all predicted targets (maximum 100). Also, a search box allows filtering the results. Links to GeneCards, UniProt and ChEMBL are provided. Protein complexes are now given in full name (as in ChEMBL, one example boxed in yellow); each subunit/component is linked individually to GeneCards and UniProt. The last column gives how many known actives on each listed target are highly similar to the query molecule based on either 2D or 3D similarity measures. These numbers are links to pages containing information about these similar molecules (refer to Figure 3). Clicking on the right-hand ‘download’ icon saves a ZIP archive on the user's computer including two files. One file contains all known actives on the relative target similar in 2D to the query molecule; the other file contains all known actives on the same target similar in 3D to the query molecule. Predictions obtained from molecules active on homologous (e.g. ortholog) proteins are tagged ‘(by homology)’.

Figure 3.

Known actives output pages are tabulated lists of molecules experimentally defined as active on the protein of interest (here the tyrosine-protein kinase JAK1) that are highly similar to the query molecule (recalled on the top-left box, here: a pyrrolopyrazine JAK inhibitor from patent US2014155376A1, not included in ChEMBL23) according to 3D (panel A) or 2D (panel B) measures. These pages are obtained by clicking on the number of known actives in the previous prediction output page (see Figure 2). All molecules have similarity values to the query compound above the defined thresholds (0.65 Tanimoto index on FP2 for 2D, and 0.85 Manhattan-based measure on ES5D for 3D) and ranked from the most to less similar. A link to the ChEMBL compound report card is provided for each compound by clicking on the ChEMBL ID. The major novelty on the known actives page are the interoperability icons for straightforward submission of the known active compounds (or the query molecule) to the in-house webtools SwissSimilarity (‘twins’), SwissTargetPrediction (‘target’), SwissADME (‘pill’). It is also possible to get the molecules SMILES. By clicking the ‘Export table’ icon, known actives can be downloaded as a CSV file containing ChEMBL ID, SMILES, similarity value to the query molecule (Tanimoto or Manhattan-based measures, for 2D or 3D respectively) and the source species of the homologous experimentally determined target (if this applies).