Optimization of adenosine 5'-carboxamide derivatives as adenosine receptor agonists using structure-based ligand design and fragment screening.
Optimization of adenosine 5'-carboxamide derivatives as adenosine receptor agonists using structure-based ligand design and fragment screening.
复制标题
DOI：
10.1021/jm300095s
复制
发表时间：
2012-05-10
影响因子：
7.3
通讯作者：
Katritch, Vsevolod
中科院分区：
文献类型：
--
作者：
Tosh, Dilip K.;Phan, Khai;Gao, Zhan-Guo;Gakh, Andrei A.;Xu, Fei;Deflorian, Francesca;Abagyan, Ruben;Stevens, Raymond C.;Jacobson, Kenneth A.;Katritch, Vsevolod
G蛋白偶联受体（GPCR）的结构在发现新的拮抗剂和反向激动剂调节该重要的临床靶家族的信号传导中具有已证实的效用。然而，活性状态GPCR结构对激动剂的虚拟筛选和合理优化的适用性仍有待评估。在腺苷5′衍生物的这项研究中，我们评估了激动剂结合的A2A腺苷受体（AR）结构在检索已知激动剂中的性能，然后利用该结构筛选最佳拟合相应亚口袋的新片段。生物化学和功能测定证明了包括极性杂环的新衍生物的高亲和力。结合模型还解释了一些取代基对密切相关的A1AR亚型的适度选择性增益和这些配体中的一些的修饰的激动剂功效。该研究表明，在计算机片段筛选的进一步适用性，以合理的铅优化GPCR。
Structures of G protein-coupled receptors (GPCRs) have a proven utility in the discovery of new antagonists and inverse agonists modulating signaling of this important family of clinical targets. Applicability of active-state GPCR structures to virtual screening and rational optimization of agonists, however, remains to be assessed. In this study of adenosine 5′ derivatives, we evaluated the performance of an agonist-bound A2A adenosine receptor (AR) structure in retrieval of known agonists and then employed the structure to screen for new fragments optimally fitting the corresponding subpocket. Biochemical and functional assays demonstrate high affinity of new derivatives that include polar heterocycles. The binding models also explain modest selectivity gain for some substituents toward the closely related A1AR subtype and the modified agonist efficacy of some of these ligands. The study suggests further applicability of in silico fragment screening to rational lead optimization in GPCRs.
登录
查看更多内容
影响因子：
13.8
作者：
Katritch V;Abagyan R
通讯作者：
Abagyan R
影响因子：
7.3
作者：
DALY, JW
通讯作者：
DALY, JW
影响因子：
7.3
作者：
Bosch, MP;Campos, F;Guerrero, A
通讯作者：
Guerrero, A
影响因子：
--
作者：
Fishman, P;Bar-Yehuda, S;Synowitz, M;Powell, J D;Klotz, K N;Gessi, S;Borea, P A
通讯作者：
Borea, P A
影响因子：
4.7
作者：
Katritch, Vsevolod;Kufareva, Irina;Abagyan, Ruben
通讯作者：
Abagyan, Ruben