文献类型：期刊文献

英文题名：Free energy landscape for the binding process of Huperzine A to acetylcholinesterase

作者：Bai, Fang[1,2];Xu, Yechun[3];Chen, Jing[3];Liu, Qiufeng[3];Gu, Junfeng[1];Wang, Xicheng[1];Ma, Jianpeng[4,7];Li, Honglin[8,9];Onuchic, Jose N.[5,6];Jiang, Hualiang[3,8,9]

机构：[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]Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA;[8]E China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[9]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China

年份：2013

卷号：110

期号：11

起止页码：4273

外文期刊名：PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000316238300032)】；

基金：The authors thank Profs. Joel L. Sussman and Israel Silman for providing the enzyme of TcAChE and Prof. Dayuan Zhu for providing chemical samples of HupA for our experimental validation research. The authors also thank GE Healthcare Life Sciences, Ltd. for supporting the SPR assays. This work was supported by the State Key Program of Basic Research of China (2009CB918500 and 2009CB918502), the National Natural Science Foundation of China (20721003, 20720102040, 21173076, 81222046, and 81230076), the Shanghai Committee of Science and Technology (Grant 11D22260600), the 863 Hi-Tech Program of China (Grant 2012AA020308), the National Science and Technology Major Project (2009ZX09501-001), a Scholarship Award for Excellent Doctoral Student granted by the Ministry of Education (to F.B.), the "100 Talents Project" of the Chinese Academy of Sciences (Y.X.), and the Program for New Century Excellent Talents in University [Grant NCET-10-0378 (to H.L.)]. J.N.O.'s work was supported by the Center for Theoretical Biological Physics sponsored by the National Science Foundation (NSF) (Grant PHY-0822283) and by NSF Grant MCB-1214457. J.N.O. is a scholar in Cancer Research sponsored by the Cancer Prevention and Research Institute of Texas. J.M. acknowledges support of grants from the National Institutes of Health (R01-GM067801), the National Science Foundation (MCB-0818353), and the Welch Foundation (Q-1512). Computational resources were supported by the National Supercomputing Center in Tianjin, China (Tianhe-1), the Shanghai Supercomputer Center, and the Computer Network Information Center of the Chinese Academy of Sciences. J.N.O. and J.M. acknowledge support of a grant from the International Workstation for Protein Folding and Drug Design, Shanghai Institute of Materia Medica, Chinese Academy of Sciences.

语种：英文

外文关键词：thermodynamics; flexible docking; metastable states; transition states

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.