| 查看: 512 | 回复: 1 | ||
yaoguiyang木虫 (小有名气)
|
[求助]
求助构效关系的翻译
|
|
The Cyp binding domain of CsA comprises of residues 9, 10, 11, 1 and 2; hence, altering these residues tends to have a significant effect on Cyp binding. Modifications to residues in the CN binding domain (4, 5, 6, and 7), on the other hand, influence Cyp binding indirectly through effects on conformation, but often exert a more profound affect on CN binding. The (4R)-4-[(E)-2-butenyl]-4- methyl-L-threonine (MeBmt) group at position 1 is unique in that it resides in the Cyp binding domain, yet its sidechain drapes across the CsA scaffold and ultimately into the CN binding domain (Fig. 4). In general, modifications to MeBmt tend to decrease Cyp binding. Removing or altering the stereochemistry of the 2-methyl group reduces activity, as does introducing a second methyl group at this position.54 Likewise, removing, replacing, or capping the 30- hydroxy as an ester also reduces potency.55 One case in which Cyp binding is actually improved is when the C@C double bond is replaced with a bioisosteric sulfur atom (‘MeThiaBmt’), which was found to bind to Cyp with 178% of the affinity of CsA itself.54b The [Sar]3 position lies on the periphery on the Cyp binding domain, and consequently structural changes at [Sar]3 can directly, or indirectly through conformational bias, impact Cyp binding. Substitution at the 20-, or a-carbon of [Sar]3 is extremely welltolerated, provided that it resides on the b-face to give the Re, or D-configuration; substitution on the a-face that gives the Si, or L-configuration, results in steric clashing between this substituent and the N-methyl group of [MeLeu]4, and hence an altered conformation of the CsA scaffold that does not bind Cyp as well.56 Both [D-MeAla]3CsA and [D-MePhe]3CsA bind to Cyp with affinity comparable to that of CsA,55a while [D-MeSer]3CsA binds to Cyp with over threefold greater affinity than CsA.57 This is an important attribute that has been exploited in the design of CsA-based therapeutics. |
回复此楼» 猜你喜欢
售SCI-T0P文章，我:8O.5.5.1.O.54,科目齐全,可+急
已经有5人回复
-
售SCI一区T0P文章，我:8O.55.1.O.5.4,科目齐全,可+急
已经有4人回复
-
上海工程技术大学 激光智能制造课题组 2027级博士研究生招生
已经有6人回复
-
课题组招2027级博士 上海工程技术大学 激光智能制造方向
已经有6人回复
-
现代”学阀”该如何界定
已经有14人回复
-
求合成方法
已经有8人回复
-
师弟论文见刊大半年才想起来申请专利，还能抢救一下吗？
已经有4人回复
-
有机合成以后会不会被AI改变？做科研的虫友怎么看
已经有8人回复
-
我的奶奶
已经有3人回复
yaoguiyang
木虫 (小有名气)
 |
2楼2014-11-30 11:07:14