In Silico Design and Evaluation of Carboxylesterase Inhibitors.
In Silico Design and Evaluation of Carboxylesterase Inhibitors.
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DOI：
10.1584/jpestics.r10-06
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发表时间：
2010
影响因子：
4.8
通讯作者：
Wadkins RM
中科院分区：
文献类型：
--
作者：
Stoddard SV;Yu X;Potter PM;Wadkins RM
羧酸酯酶（Carboxylesterases，CE）是一类重要的酶，催化生物解毒、农药水解和酯化药物代谢。开发CE抑制剂具有许多潜在用途，包括延长药物寿命和改变生物分布;降低或消除代谢药物的毒性;以及降低害虫对杀虫剂的抗性。在这篇综述中，我们讨论了已知的哺乳动物CE抑制剂的主要类别，并描述了我们的计算努力，设计新的支架开发新的，选择性的抑制剂。我们讨论了几种策略，在计算机抑制剂的发展，包括结构对接，数据库搜索，多维定量构效分析（QSAR），和一个新使用的方法，使用QSAR结合从头药物设计。虽然我们的研究主要集中在设计人肠道羧酸酯酶（hiCE）的特异性抑制剂，但所描述的方法通常适用于其他酶的抑制剂，包括来自其他组织和生物体的CE。
Carboxylesterases (CEs) are important enzymes that catalyze biological detoxification, hydrolysis of certain pesticides, and metabolism of many esterified drugs. The development of inhibitors for CE has many potential uses, including increasing drug lifetime and altering biodistrubution; reducing or abrogating toxicity of metabolized drugs; and reducing pest resistance to insecticides. In this review, we discuss the major classes of known mammalian CE inhibitors and describe our computational efforts to design new scaffolds for development of novel, selective inhibitors. We discuss several strategies for in silico inhibitor development, including structure docking, database searching, multidimensional quantitative structure activity analysis (QSAR), and a newly-used approach that uses QSAR combined with de novo drug design. While our research is focused on design of specific inhibitors for human intestinal carboxylesterase (hiCE), the methods described are generally applicable to inhibitors of other enzymes, including CE from other tissues and organisms.