| 查看: 430 | 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
22408，264求调剂
已经有3人回复
-
294求调剂
已经有6人回复
-
283分求调剂
已经有6人回复
-
求调剂
已经有3人回复
-
材料调剂
已经有6人回复
-
26考研调剂0710 0860
已经有4人回复
-
353求调剂
已经有4人回复
-
278求调剂
已经有4人回复
-
281求调剂
已经有9人回复
-
材料科学与工程考研
已经有8人回复
yaoguiyang
木虫 (小有名气)
 |
2楼2014-11-30 11:07:14
