Binding free energy calculations to rationalize the interactions of huprines with acetylcholinesterase
comunitat-uji-handle:10234/9
comunitat-uji-handle2:10234/7013
comunitat-uji-handle3:10234/8638
comunitat-uji-handle4:
INVESTIGACIONMetadata
Title
Binding free energy calculations to rationalize the interactions of huprines with acetylcholinesteraseDate
2018-03Publisher
Springer NatureBibliographic citation
NASCIMENTO, Érica CM; OLIVA, Mónica; ANDRÉS, Juan. Binding free energy calculations to rationalize the interactions of huprines with acetylcholinesterase. Journal of computer-aided molecular design, 2018, 1-16.Type
info:eu-repo/semantics/articlePublisher version
https://link.springer.com/content/pdf/10.1007/s10822-018-0114-1.pdfVersion
info:eu-repo/semantics/acceptedVersionSubject
Abstract
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 ... [+]
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. [-]
Investigation project
Generalitat Valenciana for PrometeoII/2014/022, Ministerio de Econo- mia y Competitividad (CTQ2015-65207-P) ; Universitat Jaume I (UJI-B2016-25) ; Generalitat Valenciana (Santiago Grisolia program 2011/040)Rights
© Springer International Publishing AG, part of Springer Nature 2018
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info:eu-repo/semantics/openAccess
http://rightsstatements.org/vocab/InC/1.0/
info:eu-repo/semantics/openAccess
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