Computational and Structural Chemistry, GlaxoSmithKline Pharmaceuticals plc, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
Curr Top Med Chem. 2011;11(15):1872-81. doi: 10.2174/156802611796391276.
GPCR binding site-directed techniques are rapidly evolving into powerful tools for modern drug discovery. Many of these approaches bridge chemistry and biology, which are inseparable concepts in nature but are often treated as separate worlds in drug discovery and science in general. This review shows with several examples how focusing on the binding site(s) has a clear advantage when it comes to establishing sequence-correlated pharmacological profiles. By organizing and comparing sequence and structural data it is possible to "borrow" SAR from similar targets to increase the speed of lead-finding and, potentially, to produce ligands for previously intractable receptors. Sequence motifs correlated with ligands can be applied in the design of target-specific focused libraries that are both efficient and cost-effective and should provide increased hit-rates over diversity screening. Furthermore, in the optimization phase, the binding motif approach offers the possibility to identify quickly the most likely off-target candidates to be chosen for selectivity screening, as well as potentially characterizing those pockets which may best be exploited for improved selectivity.
G 蛋白偶联受体结合位点导向技术正在迅速发展成为现代药物发现的有力工具。这些方法中的许多方法将化学和生物学联系起来，这在自然界中是不可分割的概念，但在药物发现和一般科学中通常被视为两个独立的领域。本综述通过几个例子表明，当涉及到建立与序列相关的药理学特征时，关注结合位点具有明显的优势。通过组织和比较序列和结构数据，可以从类似的靶标中“借用”SAR，以加快先导化合物的发现速度，并有可能为以前难以治疗的受体产生配体。与配体相关的序列基序可应用于设计针对特定目标的集中文库，这些文库既高效又具有成本效益，并且应该比多样性筛选提供更高的命中率。此外，在优化阶段，结合基序方法提供了快速识别最有可能成为选择性筛选候选物的脱靶候选物的可能性，以及潜在地表征那些可能最好用于提高选择性的口袋。
