Web-based 3D-visualization of the DrugBank chemical space

Abstract

Background: Similarly to the periodic table for elements, chemical space offers an organizing principle for representing the diversity of organic molecules, usually in the form of multi-dimensional property spaces that are subjected to dimensionality reduction methods to obtain 3D-spaces or 2D-maps suitable for visual inspection. Unfortunately, tools to look at chemical space on the internet are currently very limited.

Results: Herein we present webDrugCS, a web application freely available at www.gdb.unibe.ch to visualize DrugBank (www.drugbank.ca, containing over 6000 investigational and approved drugs) in five different property spaces. WebDrugCS displays 3D-clouds of color-coded grid points representing molecules, whose structural formula is displayed on mouse over with an option to link to the corresponding molecule page at the DrugBank website. The 3D-clouds are obtained by principal component analysis of high dimensional property spaces describing constitution and topology (42D molecular quantum numbers MQN), structural features (34D SMILES fingerprint SMIfp), molecular shape (20D atom pair fingerprint APfp), pharmacophores (55D atom category extended atom pair fingerprint Xfp) and substructures (1024D binary substructure fingerprint Sfp). User defined molecules can be uploaded as SMILES lists and displayed together with DrugBank. In contrast to 2D-maps where many compounds fold onto each other, these 3D-spaces have a comparable resolution to their parent high-dimensional chemical space.

Conclusion: To the best of our knowledge webDrugCS is the first publicly available web tool for interactive visualization and exploration of the DrugBank chemical space in 3D. WebDrugCS works on computers, tablets and phones, and facilitates the visual exploration of DrugBank to rapidly learn about the structural diversity of small molecule drugs.Graphical abstractwebDrugCS visualization of DrugBank projected in 3D MQN space color-coded by ring count, with pointer showing the drug 5-fluorouracil.

Keywords: Chemical space; DrugBank; Fingerprints; Molecular shape; Pharmacophores; Visualization.

Graphical abstract

webDrugCS visualization of DrugBank projected in 3D MQN space color-coded by ring count, with pointer showing the drug 5-fluorouracil.

Fig. 1

Analysis of the DrugBank database. a Percentage of data variance covered by increasing numbers of PC obtained by PCA of MQN-, SMIfp-, APfp-, Xfp- and Sfp-datasets of DrugBank. b Pearson’s correlation coefficient between pairwise euclidean distances in the n-dimensional PC-subspace and the respective original MQN, SMIfp, APfp, Xfp and Sfp fingerprint spaces, calculated from analyzing 36 M molecule pairs in the DrugBank database. c Percentage of the DrugBank database considering all single occupied bins in the original fingerprint space (black), grid points in 3D-space (blue) and pixels in 2D-space (red). A bin is defined as one particular fingerprint value combination. The 3D-spaces were generated by projecting DrugBank onto a grid of 300 × 300 × 300 grid points. The 2D-maps were generated by projecting the DrugBank onto a map of 300 × 300 pixels

Fig. 2

Color coded 3D-spaces of the DrugBank chemical space obtained by taking snapshots from the webDrugCS website (www.gdb.unibe.ch). The color changes in the range blue → cyan → green → yellow → red → magenta with increasing property value. a MQN 3D-space color coded by ring count, shown with open control panel b SMIfp 3D-space color coded by the number of aromatic carbon atoms. c APfp 3D-space color coded by rotatable bond count. d Sfp 3D-space color coded by the fraction of aromatic atoms. The molecule shown in the viewer window is located in the mouse over pixel, which is marked as a white sphere in the image

Fig. 3

The webDrugCS website and its functionalities. a Starting page of the webDrugCS. MQN, SMIfp, APfp, Xfp and Sfp 3D-spaces of the DrugBank database can be accessed by clicking on respective buttons. A list of molecules to be mapped on any 3D-space of the DrugBank database can be entered (format: SMILES) into the text box provided in the lower part of the page. See main text for the exact input format and details. b Interactive visualization window for MQN 3D-spaces obtained by clicking the button corresponding to MQN in the starting page. The 3D-space is shown with color coding using HBA atom count. On mouse over the panel at top left displays the molecule at the corresponding grid point. The example shown is cyproheptadine. c The DrugBank page for cyproheptadine was obtained by clicking the drug code displayed in the left panel in b. d Multifingerprint browser window for DrugBank with the cyproheptadine as query, obtained by clicking the “Link to browser” option in the control panel (top right panel in b). e Results window displaying the MQN-nearest neighbors of the query cyproheptadine in DrugBank

Fig. 4

Mapping of 20 DrugBank comopunds annotated with β1-adrenergic receptor antagonist activity in ChEMBL using the extrenal library option in webDrugCS. The 20 extrenal compounds are shown as white dots, overlayed on DrugBank shown in color-coded representation. Heavy atom count color coding was used for the MQN map (a), SMIfp map (b), APfp map (c) and Xfp map (d), while the N–C=C substructure cound is used for Sfp (e). Four of the 20 selected drugs are shown in e