Abstract
Hit finding, scaffold hopping, and structure–activity relationship studies are important tasks in rational drug discovery. Implementation of these tasks strongly depends on the availability of compounds similar to a known bioactive molecule. SwissSimilarity is a web tool for low-to-high-throughput virtual screening of multiple chemical libraries to find molecules similar to a compound of interest. According to the similarity principle, the output list of molecules generated by SwissSimilarity is expected to be enriched in compounds that are likely to share common protein targets with the query molecule and that can, therefore, be acquired and tested experimentally in priority. Compound libraries available for screening using SwissSimilarity include approved drugs, clinical candidates, known bioactive molecules, commercially available and synthetically accessible compounds. The first version of SwissSimilarity launched in 2015 made use of various 2D and 3D molecular descriptors, including path-based FP2 fingerprints and ElectroShape vectors. However, during the last few years, new fingerprinting methods for molecular description have been developed or have become popular. Here we would like to announce the launch of the new version of the SwissSimilarity web tool, which features additional 2D and 3D methods for estimation of molecular similarity: extended-connectivity, MinHash, 2D pharmacophore, extended reduced graph, and extended 3D fingerprints. Moreover, it is now possible to screen for molecular structures having the same scaffold as the query compound. Additionally, all compound libraries available for screening in SwissSimilarity have been updated, and several new ones have been added to the list. Finally, the interface of the website has been comprehensively rebuilt to provide a better user experience. The new version of SwissSimilarity is freely available starting from December 2021.
Highlights
Drug discovery is unarguably a very complex, expensive, labor-intensive, and timeconsuming endeavor
Ligand-based virtual screening searches for small molecules that are similar to the known active ligands, exploiting the similarity principle, which claims that similar compounds are prone to have similar bioactivities
For 3D fingerprinting, the major protonation state at pH 7.4 was calculated by JChem Microservices and further submitted for conformers generation, which was achieved by RDkit for extended 3D fingerprint (E3FP) fingerprints and by JChem Microservices for ES5D vectors (20 conformations in total, for the sake of consistency with the previous SwissSimilarity version [3])
Summary
Drug discovery is unarguably a very complex, expensive, labor-intensive, and timeconsuming endeavor. Scientific progress in the field of protein structure elucidation as well as the development of computational methodologies stimulated the advent of rational drug discovery and virtual screening The latter is an in silico technique to search within large chemical libraries for compounds that are likely to be active on a particular target. Our web tool was used to find possible drug repurposing options to treat Alzheimer’s disease [10] and SARS-CoV-2 infection [11] As another useful application of SwissSimilarity, the website was employed to search for compounds similar to a novel inhibitor of PKMYT1 kinase from the library of crystallized molecules in order to compare the predicted binding mode of the discovered compound with those available for similar molecules crystallized in complex with kinases [12]. The interface of the website was comprehensively rebuilt in order to provide a better user experience
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