ArticleProceedings of the National Academy of Sciences of the United States of America2013
Free energy landscape for the binding process of Huperzine A to acetylcholinesterase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed.
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- Determination of Multidirectional Pathways for Ligand Release from the Receptor: A New Approach Based on Differential Evolution.Journal of chemical theory and computation · 2022Article
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- Computational Methods for Structure-Based Drug Design Through System Biology.Methods in molecular biology (Clifton, N.J.) · 2022Article
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- Endophytic Fungal Community ofMolecules (Basel, Switzerland) · 2021Article
- Network Pharmacology-Based and Experimental Identification of the Effects of Paeoniflorin on Major Depressive Disorder.Frontiers in pharmacology · 2021Article
- Uncovering the Protective Mechanism of the Volatile Oil ofEvidence-based complementary and alternative medicine : eCAM · 2021Article
- Thermodynamics and Kinetics of Drug-Target Binding by Molecular Simulation.Chemical reviews · 2020Review
- Structure of MNature · 2020Article
- The binding proximity of methyl β-lilacinobioside isolated fromSaudi journal of biological sciences · 2018Article
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Authors and funding
10 authors.
Funding
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.
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