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

被引：65

作者：

Neves, Bruno J. ^{[1
]}

Dantas, Rafael F. ^{[2
]}

Senger, Mario R. ^{[2
]}

Melo-Filho, Cleber C. ^{[1
]}

Valente, Walter C. G. ^{[2
]}

de Almeida, Ana C. M. ^{[2
]}

Rezende-Neto, Joao M. ^{[2
]}

Lima, Elid F. C. ^{[2
]}

Paveley, Ross ^{[3
]}

Furnham, Nicholas ^{[3
]}

Muratov, Eugene ^{[4
]}

Kamentsky, Lee ^{[5
]}

Carpenter, Anne E. ^{[5
]}

Braga, Rodolpho C. ^{[1
]}

Silva-Junior, Floriano P. ^{[2
]}

Andrade, Carolina Horta ^{[1
]}

机构：

[1] Univ Fed Goias, Fac Farm, LabMol Lab Mol Modeling & Drug Design, Rua 240,Qd 87,Setor Leste Univ, BR-74605510 Goiania, Go, Brazil

[2] Fundacao Oswaldo Cruz, Inst Oswaldo Cruz, LaBECFar Lab Bioquim Expt & Computac Farm, Ave Brasil,4365, BR-21040900 Rio De Janeiro, RJ, Brazil

[3] London Sch Hyg & Trop Med, Dept Infect & Immun, London WC1E 7HT, England

[4] Univ N Carolina, Eshelman Sch Pharm, Lab Mol Modeling, Chapel Hill, NC 27955 USA

[5] Broad Inst Massachusetts Inst Technol & Harvard, Imaging Platform, Cambridge, MA 02142 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 15期

基金：

美国国家卫生研究院;

关键词：

THIOREDOXIN GLUTATHIONE-REDUCTASE; ANTICANCER DRUGS; IN-VITRO; MANSONI; GENOME; PRAZIQUANTEL; FEATURES; MODELS; LIGAND; SELENOCYSTEINE;

D O I：

10.1021/acs.jmedchem.5b02038

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：7075 / 7088

页数：14

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