克鲁兹锥虫
药物发现
高通量筛选
表型筛选
计算生物学
恰加斯病
生物
药品
体内
药物开发
选择(遗传算法)
药物靶点
生物信息学
表型
药理学
计算机科学
遗传学
基因
病毒学
机器学习
万维网
寄生虫寄主
作者
Martine Keenan,Paul W. Alexander,Jason H. Chaplin,Michael J. Abbott,Hugo Diao,Zhisen Wang,Wayne M. Best,Catherine Perez,Scott Cornwall,Sarah Keatley,R.C.A. Thompson,Susan A. Charman,Karen L. White,Eileen Ryan,Gong Chen,Jean‐Robert Ioset,Thomas W von Geldern,Eric Chatelain
出处
期刊:Future Medicinal Chemistry
[Newlands Press Ltd]
日期:2013-10-01
卷期号:5 (15): 1733-1752
被引量:22
摘要
Background: Inhibitors of Trypanosoma cruzi with novel mechanisms of action are urgently required to diversify the current clinical and preclinical pipelines. Increasing the number and diversity of hits available for assessment at the beginning of the discovery process will help to achieve this aim. Results: We report the evaluation of multiple hits generated from a high-throughput screen to identify inhibitors of T. cruzi and from these studies the discovery of two novel series currently in lead optimization. Lead compounds from these series potently and selectively inhibit growth of T. cruzi in vitro and the most advanced compound is orally active in a subchronic mouse model of T. cruzi infection. Conclusion: High-throughput screening of novel compound collections has an important role to play in diversifying the trypanosomatid drug discovery portfolio. A new T. cruzi inhibitor series with good drug-like properties and promising in vivo efficacy has been identified through this process.
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