Investigations into the Origin of the Molecular Recognition of Several Adenosine Deaminase Inhibitors
Investigations into the Origin of the Molecular Recognition of Several Adenosine Deaminase Inhibitors
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DOI：
10.1021/jm101286g
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发表时间：
2011-01-13
影响因子：
7.3
通讯作者：
Fischer, Bilha
中科院分区：
文献类型：
--
作者：
Gillerman, Irina;Fischer, Bilha
腺苷脱氨酶抑制剂 (ADA, EC 3 5 4 4) 是治疗各种健康疾病的潜在治疗药物 之前已鉴定出几种高效抑制剂，但它们表现出不可接受的毒性 我们进行了一项涉及一系列 C2 或 C8 取代的嘌呤核苷类似物的 SAR 研究，旨在发现毒性较小的较弱的抑制剂 我们发现星云碱 C8 位的任何取代都会导致然而，几种 2-取代-腺苷、8-氮杂-腺苷和星云碱类似物表现出抑制活性。具体而言，2-Cl-嘌呤核苷、8-氮杂-2-硫己基腺苷、2-硫己基腺苷和 2-MeS-嘌呤核苷被发现是 ADA 的竞争性抑制剂，K-i 值为 25，分别为 22、6 和 3 mu M 我们得出的结论是，电子参数不是 ADA 的主要识别决定因素，而是空间参数。适合 ADA 疏水口袋并改善与酶的氢键的 C2 取代基是良好的抑制剂。此外，关于 C4'-C5' 键的 gg 旋转异构体显然是重要的识别决定因素
Inhibitors of adenosine deaminase (ADA, EC 3 5 4 4) are potential therapeutic agents for the treatment of various health disorders Several highly potent inhibitors were previously identified, yet they exhibit unacceptable toxicities We performed a SAR study involving a series of C2 or C8 substituted purine-riboside analogues with a view to discover less potent inhibitors with a lesser toxicity We found that any substitution at C8 position of nebularine resulted in total loss of activity toward calf intestinal ADA However several 2-substituted-adenosine, 8-aza-adenosine, and nebularine analogues exhibited inhibitory activity Specifically, 2-Cl-purine riboside, 8-aza-2-thiohexyl adenosine, 2-thiohexyl adenosine, and 2-MeS-purine riboside were found to be competitive inhibitors of ADA with K-i values of 25, 22, 6, and 3 mu M, respectively We concluded that electronic parameters are not major recognition determinants of ADA but rather steric parameters A C2 substituent which fits ADA hydrophobic pocket and improves H-bonding with the enzyme makes a good inhibitor In addition, a gg rotamer about C4'-C5' bond is apparently an important recognition determinant