Frequently Asked Questions

SwissBioisostere provides information on more than 25 million molecular replacements that have been extracted from literature. Besides the information on how often such replacements were observed in the past, we also provide statistics on the impact of these molecular replacements on compounds' activity. This knowledge might be of particular interest for drug discovery projects.

Classical applications include the use of these data for lead optimization to get some ideas on how a particular moiety in a current lead molecule could be replaced to improve important parameters, such as to increase potency, to correct ADME or toxicity profiles, just to cite a few.

Another typical usage of SwissBioisostere is scaffold-hopping, i.e. searching possible exchanges of the central core of a molecule of interest to generate new chemotypes or to solve an intellectual property issue, for instance. The possibility to query for a particular replacement that has been reported in literature as truely bioisosteric, might give an insight into the conditions in which replacements were able to retain bioactivity or not.

The underlying data of SwissBiosisostere have been mined from the ChEMBL database (currently version 28). The ChEMBL database is an open-access database hosted by the European Bioinformatics Institute. The core information requested by SwissBioisostere on structure and bioactivity of druglike small molecules was retrieved only from highest curated entries of ChEMBL.

Replacements have been extracted by identifying so called Matched Molecular Pairs (MMP); pairs of molecules that differ from each other by a single structural moiety only. We use a modified version of the Hussain and Rea algorithm (JCIM 2010) to do so. We made several adaptation from the original implementation of MMP. The detection of replacements for exocyclic double bonds is one example among others

The current version of the ChEMBL database was downloaded and filtered to keep only data with higher scores on curated bioactivity values. Assays were kept if a curator of the ChEMBL database annotated that the observed effect could be directly related to an interaction with a particular molecularly defined target. Some assays were removed as their annotated bioactivity data contained obviously erroneous entries.

We extracted structures, experimental bioactivity, assay, target and target class information from the ChEMBL data. If more than one target was attributed to a particular assay all mentioned targets were stored as an ensemble of targets belonging to this particular assay. The data were split into subsets of entries corresponding to a particular assay ID. Members of such a subset have been measured in the same assay under the same conditions. MMP identification has been performed within these subsets.

The data contains four activity types (IC50, EC50, Ki, or Kd) and molecular/physchem descriptors, i.e. log P, tPSA, and molecular weight. Compounds were standardized by removing salt or solvent, and by defining a formal charge for particular substructures. Molecules were neutralized by protonating acids and deprotonating bases, and one canonical tautomer per compound was defined. The chemical context in which an attachment point was located has been annotated during the extraction of a fragment. Molecular information used by the algorithm was encoded in a canonical SMILES string. These steps were performed using ChemAxon JChem Engine.

There are several ways to input your structure:

  • Draw the chemical structure in the MarvinJS sketcher (cf. Tutorials).
  • Write or paste a SMILES on the SMILES text box, below the sketcher (cf. Help).
  • The import capacity of MarvinJS (upper toolbar or ctrl+o, cf. Help) allows you to open a local file or fetch on-line a molecule in more than 20 chemical formats including MOL, SDF, SMILES and even IUPAC or common names of drugs, for instance (cf. ChemAxon docs - Import Dialog).
  • SMILES or molecule names can also be directly pasted (ctrl+v) in the Canvas (main window) of the sketcher. For more on MarvinJS, please refer to ChemAxon docs - MarvinJS User Guide.
Once your molecule is drawn, make it a fragment by adding up to three attachment points with R-group(s) (cf. next question in the FAQ, Help & Tutorials).

Place attachment points: R1 for a side chain; R1 and R2 for a linker; R1, R2 and R3 for a scaffold. (cf. Tutorials & Help sections.) A limit to a maximum of 15 heavy atoms was set for linkers and scaffolds in order to avoid combinatorial explosion. So if any bigger linker or scaffold is inputted, no data will be found. However, there is no size limit for side chains.

We provide several levels of information about replacements in our database. If you query for possible replacements of a particular fragment, you will receive a high-level overview about all replacing fragments found in the literature.

For each, more detailed information can be found by clicking the image of the corresponding chemical structure. We consider a replacement "better", if the resulting compound shows a significantly higher experimental activity in the assay than its parent compound, i.e. 0.5 log difference in pIC50 or pKi (3.2 fold). Likewise, "worse" replacements caused the resulting compounds to be measured at least 0.5 log units less potent than the parent compounds. Everything in between is considered not to change bioactiviy significantly and are tagged as "Similar".

The detailed overview offers you the possibility to aggregate the data on different levels. The table is sortable and searchable to focus on results for particular target classes, targets, or even assay ids. Each of these steps is decreasing noise in the data, as, for example, different assay conditions might have an impact if an exchange was considered positive or not. Additionally, we provide several filter options, e.g. to highlight only binding assay data or replacements of pairs in which stereochemistry is fully annotated.

Basically the table of replacements offers two kinds of external links. The first one are links to the databases of origin. Any molecule ID or assay ID can be clicked to access the corresponding ChEMBL page providing further details and possibilities for additional investigations. Similarily, The PubMedID links any assays to its original publication. The second kind of links are the so-called interoperability icons below the compound structures.

These little red icons enable a one-click submission of the molecule (either the parent or the resulting compound) to another Web tool of SwissDrugDesign. At the moment, SwissSimilarity (twins icon for ligand-based virtual screening), SwissTargetPrediction (target icon for prediction of possible protein targets), SwissADME (pill icon for calculation of parameters relevant for physchem, ADME and medicinal chemistry) are reachable this way.

It also works the other way around! SwissBiosisostere is possible to reach from these tools by clicking the hexagon icon . Any output molecule of SwissSimilarity, SwissTargetPrediction or SwissADME is automatically imported in the sketcher of SwissBioisosetere in a new tab, where the user is free to select the fragment for which to find replacements by deleting the rest of the molecule and placing the (one, two or three) attachment points (R1, R2, R3).

There are multiple ways to share and save results after querying SwissBioisostere. First, users have the possibility to export results as formatted text, PDF, spreadsheet or printed form by clicking the corresponding buttons above the result tables. It is also possible to share the URL of a result page. The search is restarted when providing a browser with a link and hence the same time is required before the Web page is displayed. Please note, that outputs of SwissBioisostere are provided openly. However, any warranty about confidentiality cannot be given. Please refer to the Terms of Use.

Absolutely. Please watch our tutorial videos in the Tutorials section and have also a look at our static help page in the Help section.

The requirements are really minimal for the website to work perfectly. Please upgrade to the latest version of Mozilla Firefox or Google Chrome. Please ensure that pop-up windows and javascript are allowed.

Please also ensure that both your browser and your infrastructure allow web services. Especially if you get this error: "Request has not been sent. The browser may block the request if it violates the same origin policy.".

Putting the web site under HTTPS is in our plans. However, for technical reasons and web service dependencies, this cannot be achieved immediately. It will be in the future.

SwissBioisostere is developed, hosted and maintained by the Molecular Modelling Group of the SIB Swiss Institute of Bioinformatics in Lausanne, Switzerland. One objective of the group consists in providing freely accessible web tools for computer-aided drug design (CADD) to be used by both specialists and non-experts of the scientific community worldwide. In that context, the SwissBioisostere database is one piece of the SwissDrugDesign project, which aims at providing a Web environment covering as many aspects of CADD as possible to support drug discovery and development.

In case the results of SwissBiosistere were useful for your research, please cite the reference articles. Refer to the Citing page.

Please read the Terms of Use.

For technical reasons, we display only the 12'000 first candidate fragments. This threshold only affects the request of replacements to phenyl.

Please do not hesitate to contact us.