Exploring the active site of phenylethanolamine N-methyltransferase with 1,2,3,4-tetrahydrobenz[h] isoquinoline inhibitors
Exploring the active site of phenylethanolamine N-methyltransferase with 1,2,3,4-tetrahydrobenz[h] isoquinoline inhibitors
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DOI：
10.1016/j.bmc.2006.11.010
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发表时间：
2007-02-01
影响因子：
3.5
通讯作者：
Criscione, Kevin R.
中科院分区：
文献类型：
--
作者：
Grunewald, Gary L.;Seim, Mitchell R.;Criscione, Kevin R.
1,2,3,4-Tetrahydrobenz[h]isoquinoline (THBQ, 11) 是一种有效的苯乙醇胺 N-甲基转移酶 (PNMT) 抑制剂。对接研究表明，11（hPNMT K-i = 0.49 μM）与 1,2,3,4-四氢异喹啉（5，hPNMT Ki = 5.8 μM）相比增强的 PNMT 抑制效力可能是由于与 PNMT 活性位点中的 Val53、Met258、Val272 和 Val269 的疏水相互作用所致。这些研究还表明，在 11 的 7 位上添加能够与酶形成氢键的取代基可能会导致化合物 (14-18) 具有增强的 PNMT 抑制效力。然而，这些化合物实际上对 PNMT 的效力低于 11。此外，7-溴-THBQ（19，hPNMT Ki = 0.22 mM）具有不能与酶形成氢键的亲脂性 7-取代基，其对 PNMT 的效力是 11 的两倍。这再次说明了先导化合物优化对接研究的局限性。 (c) 2006 Elsevier Ltd. 保留所有权利。
1,2,3,4-Tetrahydrobenz[h]isoquinoline (THBQ, 11) is a potent, inhibitor of phenylethanolamine N-methyltransferase (PNMT). Docking studies indicated that the enhanced PNMT inhibitory potency of 11 (hPNMT K-i = 0.49 mu M) versus 1,2,3,4-tetrahydroisoquinoline (5, hPNMT Ki = 5.8 mu M) was likely due to hydrophobic interactions with Val53, Met258, Val272, and Val269 in the PNMT active site. These studies also suggested that the addition of substituents to the 7-position of 11 that are capable of forming hydrogen bonds to the enzyme could lead to compounds (14-18) having enhanced PNMT inhibitory potency. However, these compounds are in fact less potent at PNMT than 11. Furthermore, 7-bromo-THBQ (19, hPNMT Ki = 0.22 mM), which has a lipophilic 7-substituent that cannot hydrogen bond to the enzyme, is twice as potent at PNMT than 11. This once again illustrates the limitations of docking studies for lead optimization. (c) 2006 Elsevier Ltd. All rights reserved.