Ligand-supported homology modeling of G-protein-coupled receptor sites: Models sufficient for successful virtual screening
Ligand-supported homology modeling of G-protein-coupled receptor sites: Models sufficient for successful virtual screening
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DOI：
10.1002/anie.200352776
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发表时间：
2004-01-01
影响因子：
16.6
通讯作者：
Klebe, G
中科院分区：
文献类型：
--
作者：
Evers, A;Klebe, G
各种基因组测序项目的最新进展已经打开了数千种蛋白质序列的闸门，这些序列可能是药物发现的新靶点。[1]因此，计算机技术需要足够准确的蛋白质结构的可靠预测，以作为基于结构的药物设计的平台。我们开发了一种新的方法，通过同源性来模拟蛋白质。因为结合的配体分子起到约束作用，所以产生了蛋白质结合位点的更相关的几何形状。[2]通过将生物活性配体的信息作为空间约束（Figure 1），我们的方法移动的（Modeling Binding Sites Including Ligand Information Explanatory）已经通过复制结构已知的蛋白质的结合位点模型进行了参数化和验证。随后，我们将这种方法应用于神经激肽-1（NK 1）受体拮抗剂的发现。该蛋白质属于G蛋白偶联受体（GPCR）家族，在亚微摩尔范围内具有结合亲和力的配体。
Recent advances in the various genome-sequencing projects have opened the floodgates to thousands of protein sequences that are possibly new targets for drug discovery.[1] Accordingly, computer techniques are required for the reliable prediction of protein structures accurate enough to serve as a platform for structure-based drug design. We have developed a new approach that models proteins by homology. Because the bound ligand molecules serve as restraints, more relevant geometries of protein binding sites result.[2] Initial homology models of the target protein are optimized iteratively by including information about bioactive ligands as spatial restraints (Figure 1).Our approach, MOBILE (Modeling Binding Sites Including Ligand Information Explicitly), has been parameterized and validated by reproducing binding-site models of proteins for which the structure is actually known. Subsequently, we applied this method to the discovery of neurokinin-1 (NK1) receptor antagonists. A ligand with binding affinity in the submicromolar range was found for this protein, which belongs to the family of G-protein-coupled receptors (GPCRs).