2024-03-29T12:14:05Zhttps://repositori.uji.es/oai/requestoai:repositori.uji.es:10234/1680322024-03-13T12:18:43Zcom_10234_7013com_10234_9col_10234_8638
Repositori UJI
author
Nascimento, Érica C. M.
author
Oliva, Mónica
author
Świderek, Katarzyna
author
Martins, João B. L.
author
Andres, Juan
2017-06-19T12:38:43Z
2017-06-19T12:38:43Z
2017-04
NASCIMENTO, Érica CM, et al. Binding Analysis of Some Classical Acetylcholinesterase Inhibitors: Insights for a Rational Design Using Free Energy Perturbation Method Calculations with QM/MM MD Simulations. Journal of Chemical Information and Modeling, 2017, vol. 57, no 4, p. 958-976.
http://hdl.handle.net/10234/168032
http://dx.doi.org/10.1021/acs.jcim.7b00037
In the present study, the binding free energy of some classical inhibitors (DMT, DNP, GNT, HUP, THA) with acetylcholinesterase (AChE) is calculated by means of the free energy perturbation (FEP) method based on hybrid quantum mechanics and molecular mechanics (QM/MM) potentials. The results highlight the key role of the van der Waals interaction for the inhibition process, since the contribution of this term to the binding free energy is almost as decisive as the electrostatic one. The analysis of the geometrical parameters and the interaction energy per residue along the QM/MM molecular dynamics (MD) simulations highlights the most relevant interactions in the different AChE–ligand systems, showing that the charged residues with a more prominent contribution to the interaction energy are Asp72 and Glu199, although the relative importance depends on the molecular size of the ligand. A correlation between the binding free energy and the number of cation−π interactions present in the systems has been established, DMT being the most potent inhibitor, capable of forming four cation−π interactions. A layer of water molecules surrounding the inhibitors has been observed, which act as bridges along a network formed by the ligands and the residues of the gorge and also between different residues. Although several hydrogen bonds between ligands and AChE do appear, no significant values of BIEs have been recorded. This behavior can be accounted for by the special features of AChE, such as the presence of several subsites of different natures in the gorge or the existence of several water molecules that act as bridges in the electrostatic interactions.
eng
Copyright © 2017 American Chemical Society
acetylcholinesterase
classical inhibitors
free energy perturbation
Binding Analysis of Some Classical Acetylcholinesterase Inhibitors: Insights for a Rational Design Using Free Energy Perturbation Method Calculations with QM/MM MD Simulations
info:eu-repo/semantics/article
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