Free energy landscape for the binding process of Huperzine A to acetylcholinesterase
文献类型：期刊论文
| 作者 | Bai, Fang1,2; Xu, Yechun3 ; Chen, Jing3; Liu, Qiufeng3; Gu, Junfeng1; Wang, Xicheng1; Ma, Jianpeng4,8; Li, Honglin7,9; Onuchic, Jose N.5,6; Jiang, Hualiang3,7,9
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| 刊名 | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
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| 出版日期 | 2013-03-12 |
| 卷号 | 110期号:11页码:4273-4278 |
| ISSN号 | 0027-8424 |
| 关键词 | thermodynamics flexible docking metastable states transition states |
| DOI | 10.1073/pnas.1301814110 |
| 文献子类 | Article |
| 英文摘要 | Drug-target residence time (t = 1/k(off), where k(off) is the dissociation rate constant) has become an important index in discovering better- or best-in-class drugs. However, little effort has been dedicated to developing computational methods that can accurately predict this kinetic parameter or related parameters, k(off) and activation free energy of dissociation (Delta G(off)(not equal)). In this paper, energy landscape theory that has been developed to understand protein folding and function is extended to develop a generally applicable computational framework that is able to construct a complete ligand-target binding free energy landscape. This enables both the binding affinity and the binding kinetics to be accurately estimated. We applied this method to simulate the binding event of the anti-Alzheimer's disease drug (-)-Huperzine A to its target acetylcholinesterase (AChE). The computational results are in excellent agreement with our concurrent experimental measurements. All of the predicted values of binding free energy and activation free energies of association and dissociation deviate from the experimental data only by less than 1 kcal/mol. The method also provides atomic resolution information for the (-)-Huperzine A binding pathway, which may be useful in designing more potent AChE inhibitors. We expect this methodology to be-widely applicable to drug discovery and development. |
| WOS关键词 | MOLECULAR-DYNAMICS SIMULATIONS ; TARGET RESIDENCE TIME ; DRUG DISCOVERY ; PROTEIN ; MECHANISM ; RECOGNITION ; GORGE ; SOLVATION ; KINETICS ; LIGANDS |
| 资助项目 | GE Healthcare Life Sciences, Ltd.[00000000] ; State Key Program of Basic Research of China[2009CB918500] ; State Key Program of Basic Research of China[2009CB918502] ; National Natural Science Foundation of China[20721003] ; National Natural Science Foundation of China[20720102040] ; National Natural Science Foundation of China[21173076] ; National Natural Science Foundation of China[81222046] ; National Natural Science Foundation of China[81230076] ; Shanghai Committee of Science and Technology[11D22260600] ; 863 Hi-Tech Program of China[2012AA020308] ; National Science and Technology Major Projec[2009ZX09501-001] ; Ministry of Education[00000000] ; Chinese Academy of Sciences[00000000] ; Program for New Century Excellent Talents in University[NCET-10-0378] ; Center for Theoretical Biological Physics[00000000] ; National Science Foundation (NSF)[PHY-0822283] ; National Science Foundation (NSF)[MCB-1214457] ; National Science Foundation (NSF)[MCB-0818353] ; Cancer Prevention and Research Institute of Texas[00000000] ; National Institutes of Health[R01-GM067801] ; Welch Foundation[Q-1512] ; International Workstation for Protein Folding and Drug Design, Shanghai Institute of Materia Medica, Chinese Academy of Sciences[00000000] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| 出版者 | NATL ACAD SCIENCES |
| WOS记录号 | WOS:000316238300032 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277698]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物安全性评价中心 |
| 通讯作者 | Li, Honglin |
| 作者单位 | 1.Dalian Univ Technol, Dept Engn Mech, State Key Lab Struct Anal Ind Equipment, Dalian 116023, Peoples R China; 2.Dalian Univ Technol, Fac Chem Environm & Biol Sci & Technol, Dalian 116023, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Materia Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China; 4.Rice Univ, Dept Bioengn, Houston, TX 77005 USA; 5.Rice Univ, Ctr Theoret Biol Phys, Houston, TX 77005 USA; 6.Rice Univ, Dept Phys, Houston, TX 77005 USA; 7.E China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China; 8.Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA; 9.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China |
| 推荐引用方式 GB/T 7714 | Bai, Fang,Xu, Yechun,Chen, Jing,et al. Free energy landscape for the binding process of Huperzine A to acetylcholinesterase[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2013,110(11):4273-4278. |
| APA | Bai, Fang.,Xu, Yechun.,Chen, Jing.,Liu, Qiufeng.,Gu, Junfeng.,...&Jiang, Hualiang.(2013).Free energy landscape for the binding process of Huperzine A to acetylcholinesterase.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,110(11),4273-4278. |
| MLA | Bai, Fang,et al."Free energy landscape for the binding process of Huperzine A to acetylcholinesterase".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 110.11(2013):4273-4278. |
入库方式： OAI收割
来源：上海药物研究所
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