Departments of Pathology, Biological Chemistry and the Interdisciplinary Program in Medicinal Chemistry, The Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109-2216, USA.
Chem Biol Drug Des. 2013 Jan;81(1):22-32. doi: 10.1111/cbdd.12066.
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 postgenomic 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 (HTS) technology and chemical library design that are emerging to deal with these challenges.
在人类基因组测序和组装之后，新药物靶点的鉴定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方法有根本的不同，以前的方法主要是利用作用于细胞靶点的小分子配体的知识作为主要的发现引擎。“先靶标，后药理学”策略的一个后果是，许多预测的药物靶标是非酶，如支架、调节或结构蛋白，它们的活性通常依赖于蛋白质-蛋白质相互作用（PPIs）。这些类型的靶标给药物发现工作带来了独特的挑战，因为酶的周转率不能作为化合物效力的方便替代物。此外，预测配体与非酶结合如何影响蛋白质功能和/或病理生物学的变化通常具有挑战性。因此，在后基因组时代，基于分子生物学的方法可能强烈暗示靶标，但它们往往后来被指定为“不可成药”。是否可以扩大可用靶标的范围，将这些有前途但具有挑战性的非酶包括在内？在这篇综述中，我们讨论了高通量筛选（HTS）技术和化学文库设计的进展，这些进展正在出现以应对这些挑战。
