Discovery of New Anti-Schistosomal Hits by Integration of QSAR-Based Virtual Screening and High Content Screening

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• 作者：Bruno J. Neves ; Rafael F. Dantas ; Mario R. Senger ; Cleber C. Melo-Filho ; Walter C. G. Valente ; Ana C. M. de Almeida ; João M. Rezende-Neto ; Elid F. C. Lima ; Ross Paveley ; Nicholas Furnham ; Eugene Muratov ; Lee Kamentsky ; Anne E. Carpenter ; Rodolpho C. Braga ; Floriano P. Silva-Junior ; Carolina Horta Andrade
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：August 11, 2016
• 年：2016
• 卷：59
• 期：15
• 页码：7075-7088
• 全文大小：710K
• 年卷期：0
• ISSN：1520-4804

文摘

Schistosomiasis is a debilitating neglected tropical disease, caused by flatworms of Schistosoma genus. The treatment relies on a single drug, praziquantel (PZQ), making the discovery of new compounds extremely urgent. In this work, we integrated QSAR-based virtual screening (VS) of Schistosoma mansoni thioredoxin glutathione reductase (SmTGR) inhibitors and high content screening (HCS) aiming to discover new antischistosomal agents. Initially, binary QSAR models for inhibition of SmTGR were developed and validated using the Organization for Economic Co-operation and Development (OECD) guidance. Using these models, we prioritized 29 compounds for further testing in two HCS platforms based on image analysis of assay plates. Among them, 2-[2-(3-methyl-4-nitro-5-isoxazolyl)vinyl]pyridine and 2-(benzylsulfonyl)-1,3-benzothiazole, two compounds representing new chemical scaffolds have activity against schistosomula and adult worms at low micromolar concentrations and therefore represent promising antischistosomal hits for further hit-to-lead optimization.