Discovery of Potent and Selective CB2 Agonists Utilizing a Function-Based Computational Screening Protocol.
Discovery of Potent and Selective CB2 Agonists Utilizing a Function-Based Computational Screening Protocol.
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DOI：
10.1021/acschemneuro.3c00580
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发表时间：
2023-11-01
影响因子：
5
通讯作者：
Wang, Junmei
中科院分区：
文献类型：
--
作者：
Ge, Haixia;Ji, Beihong;Fang, Jiahui;Wang, Jiayang;Li, Jing;Wang, Junmei
关键词：
目前，激动剂和拮抗剂的识别是计算机辅助药物设计的一个巨大挑战。在这项工作中，我们开发了一种计算协议，使我们能够设计/筛选可能作为选择性CB 2激动剂的新型化学物质。该方案的原理是，通过计算配体与特定靶标结合的配体-残基相互作用曲线（LRIP），然后能够在统计分析和自由能计算后确定化合物的激动剂-拮抗剂功能。该计算方案成功地应用于从先导化合物开始的CB 2激动剂开发中，成功率为70%。合成的衍生物的功能通过体外功能测定来确定。此外，鉴定的有效CB 2激动剂和拮抗剂与使用已知的有效CB 2激动剂/拮抗剂鉴定的关键残基强烈相互作用。化合物6（一种有效的激动剂）的相互作用曲线的分析显示与F2.61、I186和F2.64的强相互作用，而化合物39（一种有效的拮抗剂）显示与L17、W6.48、V6.51和C7.42的强相互作用。然而，包括V3.32、T3.33、S7.39、F183、W5.43和I3.29的一些残基是CB 2激动剂和拮抗剂的热点。更重要的是，我们确定了环中的三个热点残基，包括激动剂的I186，拮抗剂的L17和两者的F183。在CB 1/CB 2合理配体设计中通常不考虑这些热点残基。总之，LRIP是一个有用的概念，在合理设计的化合物具有一定的功能。
Nowadays, the identification of agonists and antagonists represents a great challenge in computer-aided drug design. In this work, we developed a computational protocol enabling us to design/screen novel chemicals that are likely to serve as selective CB2 agonists. The principle of this protocol is that by calculating the ligand–residue interaction profile (LRIP) of a ligand binding to a specific target, the agonist–antagonist function of a compound is then able to be determined after statistical analysis and free energy calculations. This computational protocol was successfully applied in CB2 agonist development starting from a lead compound, and a success rate of 70% was achieved. The functions of the synthesized derivatives were determined by in vitro functional assays. Moreover, the identified potent CB2 agonists and antagonists strongly interact with the key residues identified using the already known potent CB2 agonists/antagonists. The analysis of the interaction profile of compound 6, a potent agonist, showed strong interactions with F2.61, I186, and F2.64, while compound 39, a potent antagonist, showed strong interactions with L17, W6.48, V6.51, and C7.42. Still, some residues including V3.32, T3.33, S7.39, F183, W5.43, and I3.29 are hotspots for both CB2 agonists and antagonists. More significantly, we identified three hotspot residues in the loop, including I186 for agonists, L17 for antagonists, and F183 for both. These hotspot residues are typically not considered in CB1/CB2 rational ligand design. In conclusion, LRIP is a useful concept in rationally designing a compound to possess a certain function.
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影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
通讯作者：
Walker, Ross C.
影响因子：
7.9
作者：
Jiang, Xingwu;Chen, Si;Lu, Weiqiang
通讯作者：
Lu, Weiqiang
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DOI：
10.1111/j.1432-1033.1995.tb20780.x
发表时间：
1995-08-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
GALIEGUE, S;MARY, S;CASELLAS, P
通讯作者：
CASELLAS, P
DOI：
10.2174/1871529x18666180206161457
发表时间：
2018
期刊：
Cardiovascular & hematological disorders drug targets
影响因子：
--
作者：
Fulmer ML;Thewke DP
通讯作者：
Thewke DP
影响因子：
4.6
作者：
Guo H;Camargo LM;Yeboah F;Digan ME;Niu H;Pan Y;Reiling S;Soler-Llavina G;Weihofen WA;Wang HR;Shanker YG;Stams T;Bill A
通讯作者：
Bill A