Journal of Computer-Aided Molecular Design

, Volume 32, Issue 5, pp 607–622 | Cite as

Binding free energy calculations to rationalize the interactions of huprines with acetylcholinesterase

  • Érica C. M. Nascimento
  • Mónica Oliva
  • Juan Andrés


In the present study, the binding free energy of a family of huprines with acetylcholinesterase (AChE) is calculated by means of the free energy perturbation method, based on hybrid quantum mechanics and molecular mechanics potentials. Binding free energy calculations and the analysis of the geometrical parameters highlight the importance of the stereochemistry of huprines in AChE inhibition. Binding isotope effects are calculated to unravel the interactions between ligands and the gorge of AChE. New chemical insights are provided to explain and rationalize the experimental results. A good correlation with the experimental data is found for a family of inhibitors with moderate differences in the enzyme affinity. The analysis of the geometrical parameters and interaction energy per residue reveals that Asp72, Glu199, and His440 contribute significantly to the network of interactions between active site residues, which stabilize the inhibitors in the gorge. It seems that a cooperative effect of the residues of the gorge determines the affinity of the enzyme for these inhibitors, where Asp72, Glu199, and His440 make a prominent contribution.


Huprines Binding free energy calculation QM/MM Stacking interactions Binding isotope effect 



We thank Prof P. Camps, Prof. F.J. Luque, and Prof. D. Muñoz-Torrero for interesting comments on the paper. The authors acknowledge the financial support of the following agencies: Generalitat Valenciana for PrometeoII/2014/022, Ministerio de Economia y Competitividad, project CTQ2015-65207-P, Universitat Jaume I for project UJI-B2016-25. E.C.M. Nascimento is grateful to the Generalitat Valencia for Santiago Grisolia program 2011/040. We also wish to thank the Servei d’Informática, Universitat Jaume I, for the generous allocation of computer time.

Compliance with ethical standards

Conflict of interest

There are no conflicts of interest to declare.

Supplementary material

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Supplementary material 1 (DOCX 35579 KB)


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Departament de Química Física i AnalíticaUniversitat Jaume ICastellónSpain

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