In search of new lead compounds for trypanosomiasis drug design: A protein structure-based linked-fragment approach
In search of new lead compounds for trypanosomiasis drug design: A protein structure-based linked-fragment approach
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DOI：
10.1007/bf00129424
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发表时间：
1992-04
影响因子：
3.5
通讯作者：
C. Verlinde;G. Rudenko;W. Hol
中科院分区：
文献类型：
--
作者：
C. Verlinde;G. Rudenko;W. Hol
提出了一种在设计周期框架内进行基于结构的缓蚀剂设计的模块化方法。该方法包括四个阶段：（1）在靶蛋白的三维结构中定义设计途径;（2）将该途径划分为子区域;（3）在每个子区域中设计互补的构建块，也称为片段;根据形状、疏水性、氢键性质和静电来定义互补性;（4）在每个子区域中设计互补的构建块，也称为片段。（4）来自不同亚区的片段连接成潜在的先导化合物。阶段（3）和（4）由力场计算定性地指导。此外，所设计的片段作为从化学数据库中检索现有化合物的条目。这种连接片段的方法已被应用于潜在的选择性抑制剂的磷酸丙糖异构酶的布氏锥虫，昏睡病的病原体的设计。
A modular method for pursuing structure-based inhibitor design in the framework of a design cycle is presented. The approach entails four stages: (1) a design pathway is defined in the three-dimensional structure of a target protein; (2) this pathway is divided into subregions; (3) complementary building blocks, also called fragments, are designed in each subregion; complementarity is defined in terms of shape, hydrophobicity, hydrogen bond properties and electrostatics; and (4) fragments from different subregions are linked into potential lead compounds. Stages (3) and (4) are qualitatively guided by force-field calculations. In addition, the designed fragments serve as entries for retrieving existing compounds from chemical databases. This linked-fragment approach has been applied in the design of potentially selective inhibitors of triosephosphate isomerase fromTrypanosoma brucei, the causative agent of sleeping sickness.