A comparative study of AutoDock and PMF scoring performances, and SAR of 2-substituted pyrazolotriazolopyrimidines and 4-substituted pyrazolopyrimidines as potent xanthine oxidase inhibitors
A comparative study of AutoDock and PMF scoring performances, and SAR of 2-substituted pyrazolotriazolopyrimidines and 4-substituted pyrazolopyrimidines as potent xanthine oxidase inhibitors
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DOI：
10.1007/s10822-009-9314-z
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发表时间：
2010-01-01
影响因子：
3.5
通讯作者：
Nagamatsu, Tomohisa
中科院分区：
文献类型：
--
作者：
Ali, Hamed I.;Fujita, Takayuki;Nagamatsu, Tomohisa
利用AutoDock 3.05和CAChe 6.1.10中涉及的两个评价函数，将4-烷基基肼- 1h -吡唑啉[3,4-d]嘧啶、4-芳基甲基肼- 1h -吡唑啉[3,4-d]嘧啶和2-取代的7h -吡唑啉[4,3-e]-1,2,4-三唑-[1,5-c]嘧啶作为潜在的黄嘌呤氧化酶抑制剂，停靠在牛乳黄嘌呤脱氢酶的活性位点上。与CAChe-PMF对接评分相比，AutoDock结合能与抑制剂IC50之间的相关系数更好。许多配体在活性位点内显示1 - 4个氢键，其中CAChe检测到的氢键在停靠构象中通过MOPAC 2002进行了定量鉴定。这些配体被停靠在酶的狭长通道中，导致钼酸盐活性部分，配体的平面芳香部分与酶之间发生氢键和静电相互作用。此外，对抑制剂之间的SAR进行了研究，发现吡唑嘧啶类似物的氧基对其活性至关重要，三环衍生物比双环衍生物更有效。详细描述了对接抑制剂的相互作用模式。
4-Alkylidenehydrazino-1H-pyrazolo[3,4-d]pyrimidines, 4-arylmethylidenehydrazino-1H-pyrazolo[3,4-d]pyrimidines, and 2-substituted 7H-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidines as potential xanthine oxidase inhibitors were docked into the active site of the bovine milk xanthine dehydrogenase using two scoring functions involved in AutoDock 3.05 and the CAChe 6.1.10. The correlation coefficiency obtained between the AutoDock binding energy and IC50 of the inhibitors was better than that obtained by the CAChe-PMF docking score. Many ligands exhibited one to four hydrogen bonds within the active site, where the detected hydrogen bonds by CAChe was identified quantitatively in the docked conformation by using MOPAC 2002. These ligands were docked into a long, narrow channel of the enzyme leading to the molybdopterin active moiety, with hydrogen bonding and electrostatic interaction between the planar aromatic moiety of the ligand and the enzyme. Furthermore, SAR among inhibitors was investigated, which revealed that the oxo group of pyrazolopyrimidine analogs is essential for its activity and the tricyclic derivatives are shown to be more potent than bicyclic ones. The mode of interaction of the docked inhibitors was described in details.