D-Tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic secretory phospholipase A2 (IIa) with antiinflammatory activity
D-Tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic secretory phospholipase A2 (IIa) with antiinflammatory activity
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DOI：
10.1002/cbic.200390029
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发表时间：
2003-03-03
期刊：
影响因子：
3.2
通讯作者：
Fairlie, DP
中科院分区：
文献类型：
--
作者：
Hansford, KA;Reid, RC;Fairlie, DP
很少有报道分泌型磷脂酶A（2）抑制剂在亚微摩尔浓度下非共价地抑制人IIa亚型（hnpsPLA（2）-IIa）。本文以简单的手性前体D-酪氨酸为原料，通过衍生化得到一系列新的hnpsPLA（2）-IIa抑制剂。2.2埃晶体结构显示抑制剂结合在酶的活性位点，通过羧酸根和酰胺氧原子螯合到Ca 2+离子，H通过酰胺NH基团键合到His 48，具有多个疏水接触和T形芳香基团-His 6相互作用。对大鼠口服给药的两种化合物也证明了抗炎活性。
Few reported inhibitors of secretory phospholipase A(2) enzymes inhibit the IIa human isoform (hnpsPLA(2)-IIa) noncovalently at submicromolar concentrations. Herein, the simple chiral precursor D-tyrosine was derivastised to give a series of potent new inhibitors of hnpsPLA(2)-IIa. A 2.2-Angstrom crystal structure shows an inhibitor bound in the active site of the enzyme, chelated to a Ca2+ ion through carboxylate and amide oxygen atoms, H bonded through an amide NH group to His48, with multiple hydrophobic contacts and a T-shaped aromatic-group-His6 interaction. Antiinflammatory activity is also demonstrated for two compounds administered orally to rats.