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Journal of Computer-Aided Molecular Design

, Volume 26, Issue 10, pp 1111–1126 | Cite as

Mapping of the interaction sites of galanthamine: a quantitative analysis through pairwise potentials and quantum chemistry

  • Nicolas Galland
  • Soleymane Kone
  • Jean-Yves Le QuestelEmail author
Article

Abstract

A quantitative analysis of the interaction sites of the anti-Alzheimer drug galanthamine with molecular probes (water and benzene molecules) representative of its surroundings in the binding site of acetylcholinesterase (AChE) has been realized through pairwise potentials calculations and quantum chemistry. This strategy allows a full and accurate exploration of the galanthamine potential energy surface of interaction. Significantly different results are obtained according to the distances of approaches between the various molecular fragments and the conformation of the galanthamine N-methyl substituent. The geometry of the most relevant complexes has then been fully optimized through MPWB1K/6-31 + G(d,p) calculations, final energies being recomputed at the LMP2/aug-cc-pVTZ(-f) level of theory. Unexpectedly, galanthamine is found to interact mainly from its hydrogen-bond donor groups. Among those, CH groups in the vicinity of the ammonium group are prominent. The trends obtained provide rationales to the predilection of the equatorial orientation of the galanthamine N-methyl substituent for binding to AChE. The analysis of the interaction energies pointed out the independence between the various interaction sites and the rigid character of galanthamine. The comparison between the cluster calculations and the crystallographic observations in galanthamine-AChE co-crystals allows the validation of the theoretical methodology. In particular, the positions of several water molecules appearing as strongly conserved in galanthamine-AChE co-crystals are predicted by the calculations. Moreover, the experimental position and orientation of lateral chains of functionally important aminoacid residues are in close agreement with the ones predicted theoretically. Our study provides relevant information for a rational drug design of galanthamine based AChE inhibitors.

Keywords

Galanthamine Hydrogen bonding Quantum chemistry Acetylcholinesterase 

Notes

Acknowledgments

This work was granted access to the HPC resources of [CCRT/CINES/IDRIS] under the allocation c2011085117 made by GENCI (Grand Equipement National de Calcul Intensif). The authors gratefully acknowledge the CCIPL (Centre de Calcul Intensif des Pays de la Loire) for grants of computer time. S. K. thank the AUF (Agence Universitaire de la Francophonie) for financial support and the LCOS (Laboratoire de Chimie Organique Structurale) of Abidjan Cocody University for its help.

Supplementary material

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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Nicolas Galland
    • 1
  • Soleymane Kone
    • 2
  • Jean-Yves Le Questel
    • 1
    Email author
  1. 1.UMR CNRS 6230, Chimie Et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UFR Sciences & TechniquesUniversité de NantesNANTES Cedex 3France
  2. 2.Laboratoire de Chimie Organique Structurale, UFR SSMTUniversité d’Abidjan-CocodyAbidjan 02Ivory Coast

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