Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A(3) Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary.
Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A(3) Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary.
复制标题
DOI：
10.1021/acs.jmedchem.1c00239
复制
发表时间：
2021-09-09
影响因子：
7.3
通讯作者：
Jeong LS
中科院分区：
文献类型：
--
作者：
Lee Y;Hou X;Lee JH;Nayak A;Alexander V;Sharma PK;Chang H;Phan K;Gao ZG;Jacobson KA;Choi S;Jeong LS
区分化合物的激动型或拮抗型行为对于合理发现选择性调节剂将是非常有用的。我们合成了截短的核苷衍生物，发现6c(Ki=2.40 nM)是一种有效的人A3腺苷受体(HA3AR)激动剂，微妙的化学修饰导致了从拮抗剂到激动剂的转变。我们通过开发新的hA3AR同源模型来解释这种转变，该模型考虑了配体的药理学特征。结合分子动力学(MD)模拟和三维结构网络分析，结果表明Thr943.36和His2727.43与Thr943.36和His2727.43的氢键可以使3‘-氨基与TM3和TM7稳定地相互作用，相应的诱导配对效应可能在激活效应中起重要作用。我们的结果为化合物在原子水平上的作用提供了更准确的理解，并为设计具有特定药理特征的新药提供了理论基础。
Distinguishing compounds’ agonistic or antagonistic behavior would be of great utility for the rational discovery of selective modulators. We synthesized truncated nucleoside derivatives and discovered 6c (Ki = 2.40 nM) as a potent human A3 adenosine receptor (hA3AR) agonist, and subtle chemical modification induced a shift from antagonist to agonist. We elucidated this shift by developing new hA3AR homology models that consider the pharmacological profiles of the ligands. Taken together with molecular dynamics (MD) simulation and three-dimensional (3D) structural network analysis of the receptor–ligand complex, the results indicated that the hydrogen bonding with Thr943.36 and His2727.43 could make a stable interaction between the 3′-amino group with TM3 and TM7, and the corresponding induced-fit effects may play important roles in rendering the agonistic effect. Our results provide a more precise understanding of the compounds’ actions at the atomic level and a rationale for the design of new drugs with specific pharmacological profiles.
登录
查看更多内容
影响因子：
7.3
作者：
Gao, ZG;Kim, SK;Jacobson, KA
通讯作者：
Jacobson, KA
影响因子：
2.7
作者：
Gao, ZG;Joshi, BV;Jacobson, KA
通讯作者：
Jacobson, KA
影响因子：
5.8
作者：
Lee, EJ;Min, HY;Lee, SK
通讯作者：
Lee, SK
影响因子：
3.6
作者：
KLOTZ, KN;LOHSE, MJ;GRIFANTINI, M
通讯作者：
GRIFANTINI, M
影响因子：
7.3
作者：
Jeong, LS;Jin, DZ;Jacobson, KA
通讯作者：
Jacobson, KA