A New Look at Chemical Molecule Similarity: SwissSimilarity Guide

SwissSimilarity is a user-friendly web tool that allows similarity analysis by comparing the properties of chemical molecules. This tool offers a variety of compound libraries to find compounds similar to a query molecule, including approved drugs (FDA-approved), known biologically active molecules, commercially available and synthesizable compounds. This tool is ideal for rapid identification of potential candidates that are structurally or pharmacophorically similar to a molecule, especially in drug discovery and drug design processes. SwissSimilarity web tool integrates with extensive molecular databases, providing highly accurate results and helping researchers save time and resources. SwissSimilarity web tool can be accessed at http://www.swisssimilarity.ch/ .

SwissSimilarity web tool offers LBVS (Literature-Based Virtual Screening) with six different methods on more than 30 chemical databases and can be used in a user-friendly way without logging in (1). SwissSimilarity offers various 2D and 3D molecular fingerprints that encode compounds in different digital formats to calculate molecular similarity, which helps to quantify chemical similarity (2). Considering the similarity principle (3), the list of compounds that SwissSimilarity outputs is expected to be enriched with molecules that exhibit the same biological activity as the query compound. Therefore, the tool can be primarily used to identify new potential biologically active compounds (hit finding), to find similar compounds with chemically different backbone structures (scaffold hopping), or to find compounds that are easily accessible for structure-activity relationship studies (QSAR). SwissSimilarity can also be useful for searching for similar compounds from commercial drugs or clinical drug candidates (e.g., to support drug repurposing) or among molecules whose experimental structures have been determined in complex with protein targets (e.g., for molecular docking studies) (4). SwissSimilarity can also be used to verify the chemical novelty of de novo designed molecules.

In the example application, the lidocaine molecule will be used. Lidocaine is a molecule with local anesthetic and antiarrhythmic properties (5).

Step 1: To obtain the SMILES format for the lidocaine molecule, go to the DrugBank site. DrugBank can be accessed via https://go.drugbank.com/ . Type “lidocaine” into the search box and perform a search.

Figure 1. General information about the lidocaine molecule in DrugBank database.

Step 2: On the page, under the heading Chemical Identifiers, the SMILES format of the lidocaine molecule is copied for use in SwissSimilarity web tool.

Figure 2. Chemical identifiers of the lidocaine molecule in DrugBank database.

Step 3: Paste the obtained SMILES format into SwissSimilarity tool. In the 2nd option, a search can be made for the desired molecule class. In the example, bioactive compounds that are similar to the lidocaine molecule will be searched. Therefore, “Bioactive” was selected. In the 3rd option, the molecule library to be searched was “ChEMBL” and the method to be used in the search was “Pharmacophore”. Optionally, you can obtain many new molecules by changing the molecule libraries and search methods. After the settings are completed, the “Start Screening” button in the 4th option is pressed and a while is waited. The results will appear on a new screen.

Figure 3. Search screen of SwissSimilarity web tool.

Step 4: The results are examined. The molecules obtained on the results screen are listed from most similar to our input molecule lidocaine to least similar. To download the data for the molecules, click on the icon next to the Retrieve data title that says CSV.

Figure 4. Results screen of SwissSimilarity web tool.

Step 5: The downloaded file is examined with a program that can open a file with the “.csv” extension, such as Excel.

Figure 5. List of molecules similar to lidocaine obtained as a result of chemical molecule similarity analysis.

When the file is examined, it is seen that 400 bioactive molecules similar to the lidocaine molecule are obtained. The first 20 molecules are given in Figure 5. Here, the first column contains the ID of the molecules obtained in the ChEMBL database, the second column contains the similarity rate of the molecules to lidocaine, and the third column contains the SMILES format of the molecules.

Similar to this search, you can obtain new molecules by using lidocaine (or the molecule you want) and changing the molecule library and search method, and you can obtain a larger molecule library by combining the results you find. You can use this library you obtain in methods such as molecular docking or QSAR/QSPR.

SwissSimilarity provides a significant advantage to researchers in critical areas such as drug discovery and design with its reliable and innovative features for chemical molecule similarity analyses. The ability to quickly detect structural and pharmacophore similarities between molecules provides a strong basis for both target-oriented approaches and data-driven discoveries. SwissSimilarity enables the practical performance of complex chemical analyses with its user-friendly interface and extensive database integration. This tool is an important resource for scientists seeking to develop new therapeutic candidates.

REFERENCES

1. Zoete, V., Daina, A., Bovigny, C., & Michielin, O. SwissSimilarity: A Web Tool for Low to Ultra High Throughput Ligand-Based Virtual Screening., J. Chem. Inf. Model., 2016, 56(8), 1399.

2. Cereto-Massagué, A.; Ojeda, M.J.; Valls, C.; Mulero, M.; Garcia-Vallve, S.; Pujadas, G. Molecular fingerprint similarity search in virtual screening. Methods 2015, 71, 58–63.

3. Kubinyi, H. Similarity and Dissimilarity: A Medicinal Chemist’s View. Perspect. Drug Discov. Des. 1998, 9, 225–252.

4. Bragina, ME., Daina, A., Perez, MAS., Michielin, O. & Zoete, V. SwissSimilarity 2021 Web Tool: Novel Chemical Libraries and Additional Methods for an Enhanced Ligand-Based Virtual Screening Experience., Int. J. Mol. Sci, 2022, 23(2), 811.

5. Karnina, R., Arif, S. K., Hatta, M., & Bukhari, A. (2021). Molecular mechanisms of lidocaine. Annals of medicine and surgery, 69, 102733.