Expanding the number of 'druggable' targets: non-enzymes and protein-protein interactions.
Expanding the number of 'druggable' targets: non-enzymes and protein-protein interactions.
复制标题
DOI：
10.1111/cbdd.12066
复制
发表时间：
2013-01
影响因子：
3
通讯作者：
Gestwicki JE
中科院分区：
文献类型：
--
作者：
Makley LN;Gestwicki JE
随着人类基因组的测序和组装，用于鉴定新药靶点的首选方法发生了巨大变化。现代策略，如全基因组关联研究（GWAS）和深度测序，与以前使用的药理学指导的方法有着根本的不同，其中小分子配体作用于其细胞靶点的知识是主要的发现引擎。“靶标优先，药理学第二”策略的结果是，许多预测的药物靶标是非酶，例如支架蛋白、调节蛋白或结构蛋白，并且它们的活性通常依赖于蛋白质-蛋白质相互作用（PPI）。这些类型的靶标给药物发现工作带来了独特的挑战，因为酶促转化不能用作化合物效力的方便替代物。此外，预测配体与非酶的结合如何影响蛋白质功能和/或病理学的变化通常是具有挑战性的。因此，在后基因组时代，靶点可能与基于分子生物学的方法密切相关，但它们后来往往被称为“不可药用”。可利用的靶点的范围是否可以扩大到包括这些有前途但具有挑战性的非酶？在这篇综述中，我们讨论了高通量筛选技术和化学库设计的进展，这些技术和化学库设计正在出现，以应对这些挑战。
Following sequencing and assembly of the human genome, the preferred methods for identification of new drug targets have changed dramatically. Modern tactics such as genome-wide association studies (GWAS) and deep sequencing are fundamentally different from the pharmacology-guided approaches used previously, in which knowledge of small molecule ligands acting at their cellular targets was the primary discovery engine. A consequence of the “target-first, pharmacology-second” strategy is that many predicted drug targets are non-enzymes, such as scaffolding, regulatory or structural proteins, and their activities are often dependent on protein-protein interactions (PPIs). These types of targets create unique challenges to drug discovery efforts because enzymatic turnover cannot be used as a convenient surrogate for compound potency. Moreover, it is often challenging to predict how ligand binding to non-enzymes might affect changes in protein function and/or pathobiology. Thus, in the post-genomic era, targets might be strongly implicated by molecular biology-based methods, yet they often later earn the designation of “undruggable.” Can the scope of available targets be widened to include these promising, but challenging, non-enzymes? In this review, we discuss advances in high throughput screening technology and chemical library design that are emerging to deal with these challenges.
登录
查看更多内容
影响因子：
7.8
作者：
Bauer, Renato A.;Wurst, Jacqueline M.;Tan, Derek S.
通讯作者：
Tan, Derek S.
影响因子：
2.7
作者：
Dalvit, C;Fogliatto, G;Stockman, B
通讯作者：
Stockman, B
影响因子：
1.6
作者：
Fei, Y. Y.;Landry, J. P.;Lam, K. S.
通讯作者：
Lam, K. S.
影响因子：
9.7
作者：
Altieri, Dario C.
通讯作者：
Altieri, Dario C.
影响因子：
--
作者：
Cummings, Maxwell D.;Farnum, Michael A.;Nelen, Marina I.
通讯作者：
Nelen, Marina I.