Discovery of Potent and Selective CB2 Agonists Utilizing a Function-Based Computational Screening Protocol
文献类型：期刊论文
| 作者 | Ge, Haixia1; Ji, Beihong3,4; Fang, Jiahui2; Wang, Jiayang1; Li, Jing2 ; Wang, Junmei3,4
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| 刊名 | ACS CHEMICAL NEUROSCIENCE
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| 出版日期 | 2023-10-12 |
| 卷号 | 14期号:21页码:3941-3958 |
| 关键词 | function-based ligand design receptor-ligandbinding profile CB1/CB2 structure-activityrelationship |
| ISSN号 | 1948-7193 |
| DOI | 10.1021/acschemneuro.3c00580 |
| 通讯作者 | Ge, Haixia(ghxzwx2012@163.com) ; Li, Jing(lijing@simm.ac.cn) ; Wang, Junmei(juw79@pitt.edu) |
| 英文摘要 | 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. |
| WOS关键词 | MOLECULAR-DYNAMICS SIMULATIONS ; ENDOCANNABINOID SYSTEM ; BIOLOGICAL EVALUATION ; CRYSTAL-STRUCTURE ; INVERSE AGONISTS ; DRUG DISCOVERY ; ATOMIC CHARGES ; FREE-ENERGIES ; MM-PBSA ; RECEPTOR |
| 资助项目 | National Institutes of Health[R01GM147673] ; National Institutes of Health[R01GM149705] ; National Science Foundation[NSF1955260] ; Natural Science Foundation of China (NSFC)[21302052] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology |
| 语种 | 英语 |
| WOS记录号 | WOS:001092736200001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/307721]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Ge, Haixia; Li, Jing; Wang, Junmei |
| 作者单位 | 1.Huzhou Univ, Sch Life Sci, Huzhou 313000, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Key Lab Receptor Res, Shanghai 201203, Peoples R China 3.Univ Pittsburgh, Computat Chem Genom Screening Ctr, Sch Pharm, Pittsburgh, PA 15261 USA 4.Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA |
| 推荐引用方式 GB/T 7714 | Ge, Haixia,Ji, Beihong,Fang, Jiahui,et al. Discovery of Potent and Selective CB2 Agonists Utilizing a Function-Based Computational Screening Protocol[J]. ACS CHEMICAL NEUROSCIENCE,2023,14(21):3941-3958. |
| APA | Ge, Haixia,Ji, Beihong,Fang, Jiahui,Wang, Jiayang,Li, Jing,&Wang, Junmei.(2023).Discovery of Potent and Selective CB2 Agonists Utilizing a Function-Based Computational Screening Protocol.ACS CHEMICAL NEUROSCIENCE,14(21),3941-3958. |
| MLA | Ge, Haixia,et al."Discovery of Potent and Selective CB2 Agonists Utilizing a Function-Based Computational Screening Protocol".ACS CHEMICAL NEUROSCIENCE 14.21(2023):3941-3958. |
入库方式： OAI收割
来源：上海药物研究所
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