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

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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.

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Notes

  1. Local correlation methods eliminate the incremental BSSE arising from electron correlation. Provided that the BSSE is small at the HF level of theory (i.e. a large basis set is used), the total BSSE is rendered practically negligible by the local correlation treatment [60, 61, 69]. On the example of the ax3:O15H–O4–O13 complex, the BSSE related to the binding energy is 1.2 and 0.2 kJ mol−1 at HF/aug-cc-pVTZ(-f)//MPWB1K/6-31 + G(d,p) and LMP2/aug-cc-pVTZ(-f)//MPWB1K/6-31 + G(d,p) levels of theory, respectively.

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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.

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  1. UMR CNRS 6230, Chimie Et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UFR Sciences & Techniques, Université de Nantes, 2, rue de la Houssinière, BP 92208, 44322, NANTES Cedex 3, France

    Nicolas Galland & Jean-Yves Le Questel

  2. Laboratoire de Chimie Organique Structurale, UFR SSMT, Université d’Abidjan-Cocody, 22, BP 582, Abidjan 02, Ivory Coast

    Soleymane Kone

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Galland, N., Kone, S. & Le Questel, JY. Mapping of the interaction sites of galanthamine: a quantitative analysis through pairwise potentials and quantum chemistry. J Comput Aided Mol Des 26, 1111–1126 (2012). https://doi.org/10.1007/s10822-012-9602-x

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