Crystallography-independent determination of ligand binding modes
Crystallography-independent determination of ligand binding modes
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DOI：
10.1002/anie.200801792
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Carlomagno, Teresa
中科院分区：
文献类型：
--
作者：
Orts, Julien;Tuma, Jennifer;Carlomagno, Teresa
在过去的几十年里，基于结构的药物设计(SBDD)已经发展成为一种强有力的工具，用于将许多低分子先导化合物优化为高效药物。[1]SBDD的原理在于将不同的化学部分结合在一起，目的是获得一种分子，在具有药物所需的药理性质的同时，在形状上与受体结合口袋互补。这一过程需要了解蛋白质/配体复合体的确切结构。目前，结构基因组学计划正在以越来越快的速度提供与生物医学相关的靶标的蛋白质结构[2]，最近的离子通道结构[3]和G蛋白偶联受体(GPCRs)[4-6]使这些蛋白质类别可以达到SBDD的范围。尽管取得了这些成功，但药物发现的日常工作往往受到获得目标蛋白质高分辨晶体结构的能力的限制，这些晶体结构与通常通过高通量筛选或基于片段的先导发现所鉴定的低亲和力配体(先导结构)形成的络合物。[1]鉴于这种限制，SBDD将受益于提供不同化学片段竞争结合到受体位点的相对定向的方法。这种方法将提供与参考配体的已知共晶结构相关的新配体或片段的蛋白质/配体结构。
Within the last few decades, structure-based drug design (SBDD) has evolved into a powerful tool for the optimization of many low-molecular-weight lead compounds into highly potent drugs.[1] The principle of SBDD lies in the combination of different chemical moieties with the aim of obtaining a molecule that, while possessing the pharmacological properties necessary for a drug, is complementary in shape to the receptor binding pocket. This process requires knowledge of the exact structure of the protein/ligand complex. At present, structural genomics initiatives provide protein structures of biomedically relevant targets at an increasing rate [2] and recent structures of ion channels [3] and G-protein-coupled receptors (GPCRs)[4–6] bring these protein classes within reach for SBDD. Despite these successes, the daily work of pharmaceutical discovery is often limited by the ability to obtain high-resolution crystal structures of the target proteins in complex with the lower affinity ligands (lead structures) that are commonly identified by high-throughput screening or by fragment-based lead discovery.[1] In view of this limitation, SBDD would benefit from methods providing the relative orientations of different chemical fragments binding competitively to a receptor site. Such an approach would provide protein/ligand structures of novel ligands or fragments in relation to the known cocrystal structure of a reference ligand.