Docking and chemoinformatic screens for new ligands and targets.
Docking and chemoinformatic screens for new ligands and targets.
复制标题
新的配体和靶标的对接和化学信息筛选。
DOI：
10.1016/j.copbio.2009.08.003
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发表时间：
2009-08
影响因子：
7.7
通讯作者：
Shoichet, Brian K.
中科院分区：
文献类型：
--
作者：
Kolb, Peter;Ferreira, Rafaela S.;Irwin, John J.;Shoichet, Brian K.
基于计算机的对接屏幕现已广泛用于发现已知结构靶标的新配体；仅在过去两年，就有超过 20 种蛋白质的配体被发现的报道。最近，研究人员还转向预测新的底物和未知功能的酶，以全新的方向进行对接。越来越多地，对接屏幕的命中率、真阳性和假阳性与经验性、高通量屏幕的命中率、真阳性和假阳性进行比较，揭示了两种技术的优点、缺点和互补性。最近 GPCR 结构的蓬勃发展使这些典型的药物靶点可用于基于结构的方法。与它们的“成药性”一致，对接屏幕返回了高命中率和有效的分子。最后，在过去的几年里，还出现了一种与对接几乎完全相反的方法；这种药理学网络方法不是从靶标的结构开始，而是从药物分子的结构开始，并询问，给定配体的化学模式，特定药物可以结合哪些靶标？这种方法回归了更古老的药理学逻辑，在预测现有药物的新“脱靶”方面取得了令人惊讶的成功。
Computer-based docking screens are now widely used to discover new ligands for targets of known structure; in the last two years alone, the discovery of ligands for over 20 proteins have been reported. Recently, investigators have also turned to predicting new substrates and for enzymes of unknown function, taking docking in a wholly new direction. Increasingly, the hit-rates, the true- and the false-positives from the docking screens are being compared to those from empirical, high-throughput screens, revealing the strengths, weaknesses and complementarities of both techniques. The recent efflorescence of GPCR structures has made these quintessential drug targets available to structure-based approaches. Consistent with their “druggability”, the docking screens have returned high hit-rates and potent molecules. Finally, in the last several years, an approach almost exactly opposite to docking has also appeared; this pharmacological network approach begins not with the structure of the target but rather those of drug molecules and asks, given a pattern of chemistry in the ligands, what targets may a particular drug bind to? This method, which returns to an older, pharmacology logic, has been surprisingly successful in predicting new “off-targets” for established drugs.
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