Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening
Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening
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DOI：
10.1021/jm030644s
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发表时间：
2004-03-25
影响因子：
7.3
通讯作者：
Banks, JL
中科院分区：
文献类型：
--
作者：
Halgren, TA;Murphy, RB;Banks, JL
Glide在数据库筛选中识别活性化合物的能力的特点是将Glide应用于9种不同的蛋白质受体。在许多情况下，两个，甚至三个，蛋白质位点被用来探测结果对位点几何形状的敏感性。为了使数据库筛选尽可能真实，筛选使用了一组"药物样"诱饵配体，这些配体被选择来代表我们认为可能在制药或生物技术公司的化合物集合中发现的化合物。本文提供了Glide 1.8、2.0和2.5版的结果。比较表明，Glide 2.5的"早期"和"全局"富集的平均测量值比Glide 1.8高3倍，比Glide 2.0高2倍多，因为处理最不好的屏幕的结果更好。这种富集的改进主要源于更广泛参数化的GlideScore 2.5功能的更好平衡，以及包含惩罚违反物理化学既定原则的配体-蛋白质相互作用的术语，特别是当它涉及带电蛋白质和配体基团暴露于溶剂时。与Rognan及其同事发表的胸苷激酶和雌激素受体的结果（J. Med. Chem. 2000，43，4759 - 4767）的比较表明，Glide 2.5的性能优于GOLD 1.1、FlexX 1.8或DOCK 4.01。
Glide's ability to identify active compounds in a database screen is characterized by applying Glide to a diverse set of nine protein receptors. In many cases, two, or even three, protein sites are employed to probe the sensitivity of the results to the site geometry. To make the database screens as realistic as possible, the screens use sets of "druglike" decoy ligands that have been selected to be representative of what we believe is likely to be found in the compound collection of a pharmaceutical or biotechnology company. Results are presented for releases 1.8, 2.0, and 2.5 of Glide. The comparisons show that average measures for both "early" and "global" enrichment for Glide 2.5 are 3 times higher than for Glide 1.8 and more than 2 times higher than for Glide 2.0 because of better results for the least well-handled screens. This improvement in enrichment stems largely from the better balance of the more widely parametrized GlideScore 2.5 function and the inclusion of terms that penalize ligand-protein interactions that violate established principles of physical chemistry, particularly as it concerns the exposure to solvent of charged protein and ligand groups. Comparisons to results for the thymidine kinase and estrogen receptors published by Rognan and co-workers (J. Med. Chem. 2000, 43, 4759-4767) show that Glide 2.5 performs better than GOLD 1.1, FlexX 1.8, or DOCK 4.01.