Fragment-Based Approaches in Drug Discovery and Chemical Biology
Fragment-Based Approaches in Drug Discovery and Chemical Biology
复制标题
DOI：
10.1021/bi3005126
复制
发表时间：
2012-06-26
期刊：
影响因子：
2.9
通讯作者：
Abell, Chris
中科院分区：
文献类型：
--
作者：
Scott, Duncan E.;Coyne, Anthony G.;Abell, Chris
基于片段的方法来寻找与蛋白质结合的新型小分子，现已在药物发现和化学生物学中牢固确立。这种方法最初主要在生物技术和制药行业的几个中心开发，现在已被制药行业和学术界广泛采用。在激酶靶点的初步成功之后，这种方法的多功能性现在已经扩展到广泛的不同蛋白质类别。在这里，我们描述了最近的片段为基础的方法，范围广泛的目标类型，包括热休克蛋白90，β-分泌酶，变构位点的人类免疫缺陷病毒蛋白酶和焦磷酸凡呢基合酶。基于片段的方法在学术研究环境中的作用也进行了审查，重点是被忽视的疾病，如结核病。将使用文献中的实例讨论片段文库的开发、片段筛选过程和随后的片段命中阐述。
Fragment-based approaches to finding novel small molecules that bind to proteins are now firmly established in drug discovery and chemical biology. Initially developed primarily in a few centers in the biotech and pharma industry, this methodology has now been adopted widely in both the pharmaceutical industry and academia. After the initial success with kinase targets, the versatility of this approach has now expanded to a broad range of different protein classes. Herein we describe recent fragment-based approaches to a wide range of target types, including Hsp90, beta-secretase, and allosteric sites in human immunodeficiency virus protease and fanesyl pyrophosphate synthase. The role of fragment-based approaches in an academic research environment is also examined with an emphasis on neglected diseases such as tuberculosis. The development of a fragment library, the fragment screening process, and the subsequent fragment hit elaboration will be discussed using examples from the literature.