QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni

• Published in: Journal of chemical information and modeling Vol. 56; no. 7; pp. 1357 - 1372
• Main Authors: Melo-Filho, Cleber C, Dantas, Rafael F, Braga, Rodolpho C, Neves, Bruno J, Senger, Mario R, Valente, Walter C. G, Rezende-Neto, João M, Chaves, Willian T, Muratov, Eugene N, Paveley, Ross A, Furnham, Nicholas, Kamentsky, Lee, Carpenter, Anne E, Silva-Junior, Floriano P, Andrade, Carolina H
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 25.07.2016
• Subjects: Animals; Anthelmintics - chemistry; Anthelmintics - metabolism; Anthelmintics - pharmacology; Chemistry; Drug Design; Drug Evaluation, Preclinical; Homeostasis; Molecular Conformation; Molecular Docking Simulation; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - chemistry; Multienzyme Complexes - metabolism; NADH, NADPH Oxidoreductases - antagonists & inhibitors; NADH, NADPH Oxidoreductases - chemistry; NADH, NADPH Oxidoreductases - metabolism; Parasites; Quantitative Structure-Activity Relationship; Regression analysis; Schistosoma mansoni - drug effects; Schistosoma mansoni - enzymology; Tropical diseases
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.6b00055

Schistosomiasis is a neglected tropical disease that affects millions of people worldwide. Thioredoxin glutathione reductase of Schistosoma mansoni (SmTGR) is a validated drug target that plays a crucial role in the redox homeostasis of the parasite. We report the discovery of new chemical scaffolds against S. mansoni using a combi-QSAR approach followed by virtual screening of a commercial database and confirmation of top ranking compounds by in vitro experimental evaluation with automated imaging of schistosomula and adult worms. We constructed 2D and 3D quantitative structure–activity relationship (QSAR) models using a series of oxadiazoles-2-oxides reported in the literature as SmTGR inhibitors and combined the best models in a consensus QSAR model. This model was used for a virtual screening of Hit2Lead set of ChemBridge database and allowed the identification of ten new potential SmTGR inhibitors. Further experimental testing on both shistosomula and adult worms showed that 4-nitro-3,5-bis(1-nitro-1H-pyrazol-4-yl)-1H-pyrazole (LabMol-17) and 3-nitro-4-{[(4-nitro-1,2,5-oxadiazol-3-yl)­oxy]­methyl}-1,2,5-oxadiazole (LabMol-19), two compounds representing new chemical scaffolds, have high activity in both systems. These compounds will be the subjects for additional testing and, if necessary, modification to serve as new schistosomicidal agents.