title: Free energy landscape for the binding process of Huperzine A to acetylcholinesterase.
abstract: 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 (ΔG(off)≠). 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.
authors: Department of Engineering Mechanics, State Key Laboratory of Structural Analysis for Industrial Equipment, and Faculty of Chemical, Environmental, and Biological Science and Technology, Dalian University of Technology, Dalian 116023, China.
authors: Fang
authors: F
authors: Bai
authors: Yechun
authors: Y
authors: Xu
authors: Jing
authors: J
authors: Chen
authors: Qiufeng
authors: Q
authors: Liu
authors: Junfeng
authors: J
authors: Gu
authors: Xicheng
authors: X
authors: Wang
authors: Jianpeng
authors: J
authors: Ma
authors: Honglin
authors: H
authors: Li
authors: José N
authors: JN
authors: Onuchic
authors: Hualiang
authors: H
authors: Jiang
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000470:Alkaloids / Q000737:chemistry* / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D055808:Drug Discovery; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D017510:Protein Folding; D012717:Sesquiterpenes / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D012717:Sesquiterpenes; C050426:huperzine A; D000110:Acetylcholinesterase