Free energy landscape for the binding process of Huperzine A to acetylcholinesterase

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-03, Vol.110 (11), p.4273-4278
• Main Authors: Bai, Fang, Xu, Yechun, Chen, Jing, Liu, Qiufeng, Gu, Junfeng, Wang, Xicheng, Ma, Jianpeng, Li, Honglin, Onuchic, José N., Jiang, Hualiang
• Format: Article
• Language: English
• Subjects: acetylcholinesterase; Acetylcholinesterase - chemistry; activation energy; Active sites; Alkaloids - chemistry; Alkaloids - therapeutic use; Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; binding capacity; Binding sites; Biological Sciences; Canyons; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - therapeutic use; dissociation; Drug design; Drug Discovery; drugs; energy; Energy value; Free energy; Humans; Kinetics; landscapes; Ligands; Pain; Physical Sciences; Prescription drugs; Protein Binding; Protein Folding; Sesquiterpenes - chemistry; Sesquiterpenes - therapeutic use; Simulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1301814110

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 ([Formula]). 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.