Computation-Enabled Structure-Based Discovery of Potent Binders for Small-Molecule Aptamers
文献类型：期刊论文
| 作者 | Zhou, Qingtong2,3,4; Zhang, Zheng1; Gao, Ling6; Li, Guanyi4,8; Zhang, Yue6; Yang, Weili9; Zhao, Yaxue8; Yang, Dehua4,10,11 ; Wang, Ming-Wei2,3,4,5; Luo, Zhaofeng1
|
| 刊名 | JOURNAL OF CHEMICAL THEORY AND COMPUTATION
 |
| 出版日期 | 2025-03-03 |
| 卷号 | 21期号:6页码:3216-3230 |
| ISSN号 | 1549-9618 |
| DOI | 10.1021/acs.jctc.4c01246 |
| 通讯作者 | Zhou, Qingtong(zhouqt@fudan.edu.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn) ; Luo, Zhaofeng(lzf@ustc.edu.cn) ; Xia, Xiaole(xiaolexia@jiangnan.edu.cn) |
| 英文摘要 | Aptamers, functional nucleic acids recognized for their high target-binding affinity and specificity, have been extensively employed in biosensors, diagnostics, and therapeutics. Conventional screening methods apply evolutionary pressure to optimize affinity, while counter-selections are used to minimize off-target binding and improve specificity. However, aptamer specificity characterization remains limited to target analogs and experimental controls. A systematic exploration of the chemical space for aptamer-binding chemicals (targets) is crucial for uncovering aptamer versatility and enhancing target specificity in practical applications, a task beyond the scope of experimental approaches. To address this, we employed a high-throughput three-stage structure-based computational framework to identify potent binders for two model aptamers. Our findings revealed that the l-argininamide (L-Arm)-binding aptamer has a 31-fold higher affinity for the retromer chaperone R55 than for L-Arm itself, while guanethidine and ZINC10314005 exhibited comparable affinities to L-Arm. In another case, norfloxacin and difloxacin demonstrated over 10-fold greater affinity for the ochratoxin A (OTA)-binding aptamer OBA3 than OTA, introducing a fresh paradigm in aptamer-target interactions. Furthermore, pocket mutation studies highlighted the potential to tune aptamer specificity, significantly impacting the bindings of L-Arm or norfloxacin. These findings demonstrate the effectiveness of our computational framework in discovering potent aptamer binders, thereby expanding the understanding of aptamer-binding versatility and advancing nucleic acid-targeted drug discovery. |
| WOS关键词 | AFFINITY BINDING ; NUCLEIC-ACIDS ; DYNAMICS ; RECOGNITION ; SPECIFICITY ; PROTEINS ; DOCKING ; DESIGN |
| 资助项目 | Key Research and Development Program of Zhejiang Province[2021ZD0203400] ; National Natural Science Foundation of China[21704064] ; Key Research and Development Project of Zhejiang Province[2023C03043] ; Key Research and Development Project of Zhejiang Province[2023SDYXS0002] ; National Key Research and Development Program of China[2021YFA0910200] ; Hainan Provincial Major Science and Technology Project[ZDKJ2021028] ; Program of Introducing Talents of Discipline to Universities[No.111-2-06] |
| WOS研究方向 | Chemistry ; Physics |
| 语种 | 英语 |
| WOS记录号 | WOS:001436078600001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316463]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zhou, Qingtong; Wang, Ming-Wei; Luo, Zhaofeng; Xia, Xiaole |
| 作者单位 | 1.Chinese Acad Sci, Hangzhou Inst Med HIM, Aptamer Select Ctr, Key Lab Zhejiang Prov Aptamers & Theranost, Hangzhou 310022, Zhejiang, Peoples R China 2.Shanghai Jiao Tong Univ, Ruijin Hosp, Res Ctr Med Struct Biol, Natl Res Ctr Translat Med Shanghai,Sch Med,State K, Shanghai 200025, Peoples R China 3.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China 4.Res Ctr Deepsea Bioresources, Sanya 572025, Hainan, Peoples R China 5.Hainan Med Univ, Engn Res Ctr Trop Med Innovat & Transformat, Sch Pharm, Minist Educ, Haikou 570228, Peoples R China 6.Jiangnan Univ, Sch Biotechnol, Key Lab Ind Biotechnol, Minist Educ, Wuxi 214122, Jiangsu, Peoples R China 7.Tianjin Univ Sci & Technol, Coll Food Sci & Engn, Tianjin 300457, Peoples R China 8.Shanghai Jiao Tong Univ, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China 9.Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Anhui, Peoples R China 10.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhou, Qingtong,Zhang, Zheng,Gao, Ling,et al. Computation-Enabled Structure-Based Discovery of Potent Binders for Small-Molecule Aptamers[J]. JOURNAL OF CHEMICAL THEORY AND COMPUTATION,2025,21(6):3216-3230. |
| APA | Zhou, Qingtong.,Zhang, Zheng.,Gao, Ling.,Li, Guanyi.,Zhang, Yue.,...&Xia, Xiaole.(2025).Computation-Enabled Structure-Based Discovery of Potent Binders for Small-Molecule Aptamers.JOURNAL OF CHEMICAL THEORY AND COMPUTATION,21(6),3216-3230. |
| MLA | Zhou, Qingtong,et al."Computation-Enabled Structure-Based Discovery of Potent Binders for Small-Molecule Aptamers".JOURNAL OF CHEMICAL THEORY AND COMPUTATION 21.6(2025):3216-3230. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。