Parasitic diseases have serious health, social, and economic impacts, especially in the tropical regions of the world [1-5]. Among parasites, protozoan parasites, such as Trypanosomacruzi, Leishmania mexicana, Plasmodium falciparum, Giardia intestinalis, and Trichomonas vaginalis, are the major disease-causing organisms. Diseases caused by protozoan parasites are responsible for a considerable mortality and morbidity, affecting more than 500 million people worldwide. Globally, the burden of protozoan diseases is increasing and has been exacerbated due to the lack of effective medication caused by the drug resistance and toxicity of current antiprotozoal agents . These limitations have prompted many researchers to search for new drugs against protozoan parasites [3-8].
Life Chemicals has designed the Antiprotozoal Screening Library of over 8,200 small-molecule screening compounds with potential antiprotozoal activity against major protozoan diseases (such as giardiasis, leishmaniasis, malaria, trichomoniasis, and trypanosomiasis, etc.).
A reference set of over 5,000 compounds with reported activity against the most dangerous protozoa was prepared based on the most reliable inhibitor databases (ChEMBL and BindingDB) with the inhibitory activity data lower than 10 μM by bioassay. A 2D fingerprint similarity search was performed using the obtained reference set against the HTS Compound Collection with the Tanimoto similarity index of > 0.8. In-house medchem filters enabled to exclude all PAINS and toxicophore-containing compounds. The full list of targeted protozoa families and species:
- Cryptosporidium parvum
- Entamoeba histolytica
- Giardia (G.intestinalis)
- Leishmania (L.amazonensis, L.braziliensis, L.chagasi, L.donovani, L.major)
- Plasmodium (P.berghei, P.falciparum)
- Schistosoma mansoni
- Toxoplasma gondii
- Trichomonas vaginalis
- Trypanosoma brucei (T.brucei(brucei & rhodesiense), T.cruzi (normal & strain CL Brener))
Then, the HTS Compound Collection was searched for analogues of molecules with known activity against different protozoa targets, using the 80 % similarity cut-off (Tanimoto) on MDL public keys fingerprints and selected compounds for the following molecular targets:
- Cannabinoid CB1 receptor
- Carbonic anhydrase I and II
- Cathepsin L endopeptidase
- Cdc2-related kinase
- Cruzipain cysteine protease
- Falcipain 2 cysteine protease
- Glutamate NMDA receptor
- Glyceraldehyde-3-phosphate dehydrogenase
- Ser/thr-protein kinase Aurora-B
- Sterol 14-alpha demethylase
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