Dept of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Room 508D, San Francisco, CA 94158-2550, United States.
Curr Opin Biotechnol. 2009 Aug;20(4):429-36. doi: 10.1016/j.copbio.2009.08.003. Epub 2009 Sep 3.
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 more than 20 proteins has been reported. Recently, investigators have also turned to predicting new substrates for enzymes of unknown function, taking docking in a wholly new direction. Increasingly, the hit rates, the true-positives, 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.
计算机对接筛选现已广泛用于发现已知结构靶标的新配体；仅在过去两年中，就有超过 20 种蛋白质的配体被发现。最近，研究人员还将目光投向了预测未知功能酶的新底物，将对接推向了全新的方向。越来越多的人将对接筛选的命中率、真阳性和假阳性与经验性高通量筛选进行比较，揭示了这两种技术的优势、劣势和互补性。最近 GPCR 结构的大量涌现使这些经典的药物靶点可用于基于结构的方法。与它们的“可成药性”一致，对接筛选返回了高命中率和有效分子。最后，在过去几年中，一种几乎完全相反的方法也出现了；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，并且在询问，给定配体中的化学模式，特定药物可能与哪些靶标结合？这种方法回归到一种更古老的药理学逻辑，在预测现有药物的新“非靶标”方面取得了惊人的成功。
