The SwissSimilarity 2021 Web Tool: Novel Chemical Libraries and Additional Methods for an Enhanced Ligand-Based Virtual Screening Experience

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.

Universal encoding of next generation DNA-encoded chemical libraries

Large Encoding Design (LED) allows for the construction of DNA-encoded chemical libraries (DELs) of unprecedented sizes and designs. LED was validated and compared with previous encoding systems for amplifiability and performance in test selections.

Systemic Evolutionary Chemical Space Exploration For Drug Discovery

Chemical space exploration is a major task of the hit-finding process during the pursuit of novel chemical entities. Compared with other screening technologies, computational de novo design has become a popular approach to overcome the limitation of current chemical libraries. Here, we reported a de novo design platform named systemic evolutionary chemical space explorer (SECSE). The platform was conceptually inspired by fragment-based drug design, that miniaturized a “lego-building” process within the pocket of a certain target. The key of virtual hits generation was then turned into a computational search problem. To enhance search and optimization, human intelligence and deep learning were integrated. Application of SECSE against PHGDH, proved its potential in finding novel and diverse small molecules that are attractive starting points for further validation. This platform is open-sourced and the code is available at http://github.com/KeenThera/SECSE.

Seleno-amino acids: A novel class of anti-tuberculosis compounds identified through modified culture screening conditions

<p>Tuberculosis continues to be a major world health problem, causing more deaths than any other bacterial disease. Long treatment durations using a complex cocktail of drugs are often associated with patient non-adherence to therapy, and this has accelerated the development of drug resistant strains. Tuberculosis drug resistance has developed to the extent that some strains are resistant to all clinically used drugs. Therefore novel tuberculosis treatment drugs are urgently required to combat these resistant strains, sterilise latent infections and reduce lengthy treatment durations. This research developed and optimised a high-throughput assay to screen chemical libraries for compounds with anti-mycobacterial activity. The assay utilised fast growing tuberculosis model species M. smegmatis expressing foreign green fluorescent protein (GFP). GFP allowed bacterial growth inhibition to be measured both by fluorescence in addition to absorbance. The assay was expanded to four different culture conditions two of which were nutrient starvation that better mimicked environmental conditions M. tuberculosis is exposed to during infection. These differential culture conditions also revealed previously unidentified mycobacterial inhibitors. Three chemical libraries totaling over 5,000 compounds were screened in the different culture conditions. Seleno-amino acids (Se-AAs), a novel class of anti-tuberculosis compounds, were discovered through screens in nutrient starvation conditions. Based on traits of strong inhibitory activity towards mycobacteria, low human cell line cytotoxicity, structural novelty and known over-the-counter sale as a non-prescription dietary supplement, the Se-AAs were chosen as a promising pharmacophore for further study. Using evidence derived from anti-sense gene knockdown, transposon mutagenesis and biochemical enzyme assays, a pro-drug hypothesis of anti-mycobacterial activity was proposed that involved Se-AAs being transported into the mycobacterial cell by nutrient uptake transporters and subsequent cleavage into catalytically active methylselenium species by lyase enzymes used in mycobacterial sulphurous amino acid metabolism. The activated methylselenium is reduced by mycobacterial redox homeostasis enzymes involved in mycobacterial oxidative defence such as alkyl hydroperoxidases, generating reactive oxygen radical products that damage mycobacterial DNA, lipids and proteins. Reduced methylselenol can be cycled back to the oxidised state by cellular mycothiones, continuously generating damaging reactive oxygen species within the mycobacterial cell. Methylselenium species also disrupt essential mycobacterial processes, such as ketosteroid catabolism and iron-sulphur cluster protein function. In summary, this research has designed and implemented a novel dual label differential culture condition assay useful in the screening and detection of chemicals with anti-tuberculosis properties. A novel structural class of anti-tuberculosis compounds with therapeutic potential, the Se-AAs, was discovered using this assay, the structure-activity relationship of the Se-AAs was explored and a three-component model of Se-AA anti-tuberculosis activity is proposed.</p>

Seleno-amino acids: A novel class of anti-tuberculosis compounds identified through modified culture screening conditions

<p>Tuberculosis continues to be a major world health problem, causing more deaths than any other bacterial disease. Long treatment durations using a complex cocktail of drugs are often associated with patient non-adherence to therapy, and this has accelerated the development of drug resistant strains. Tuberculosis drug resistance has developed to the extent that some strains are resistant to all clinically used drugs. Therefore novel tuberculosis treatment drugs are urgently required to combat these resistant strains, sterilise latent infections and reduce lengthy treatment durations. This research developed and optimised a high-throughput assay to screen chemical libraries for compounds with anti-mycobacterial activity. The assay utilised fast growing tuberculosis model species M. smegmatis expressing foreign green fluorescent protein (GFP). GFP allowed bacterial growth inhibition to be measured both by fluorescence in addition to absorbance. The assay was expanded to four different culture conditions two of which were nutrient starvation that better mimicked environmental conditions M. tuberculosis is exposed to during infection. These differential culture conditions also revealed previously unidentified mycobacterial inhibitors. Three chemical libraries totaling over 5,000 compounds were screened in the different culture conditions. Seleno-amino acids (Se-AAs), a novel class of anti-tuberculosis compounds, were discovered through screens in nutrient starvation conditions. Based on traits of strong inhibitory activity towards mycobacteria, low human cell line cytotoxicity, structural novelty and known over-the-counter sale as a non-prescription dietary supplement, the Se-AAs were chosen as a promising pharmacophore for further study. Using evidence derived from anti-sense gene knockdown, transposon mutagenesis and biochemical enzyme assays, a pro-drug hypothesis of anti-mycobacterial activity was proposed that involved Se-AAs being transported into the mycobacterial cell by nutrient uptake transporters and subsequent cleavage into catalytically active methylselenium species by lyase enzymes used in mycobacterial sulphurous amino acid metabolism. The activated methylselenium is reduced by mycobacterial redox homeostasis enzymes involved in mycobacterial oxidative defence such as alkyl hydroperoxidases, generating reactive oxygen radical products that damage mycobacterial DNA, lipids and proteins. Reduced methylselenol can be cycled back to the oxidised state by cellular mycothiones, continuously generating damaging reactive oxygen species within the mycobacterial cell. Methylselenium species also disrupt essential mycobacterial processes, such as ketosteroid catabolism and iron-sulphur cluster protein function. In summary, this research has designed and implemented a novel dual label differential culture condition assay useful in the screening and detection of chemicals with anti-tuberculosis properties. A novel structural class of anti-tuberculosis compounds with therapeutic potential, the Se-AAs, was discovered using this assay, the structure-activity relationship of the Se-AAs was explored and a three-component model of Se-AA anti-tuberculosis activity is proposed.</p>