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

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 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.

journal_name

J Comput Aided Mol Des

journal_title

Journal of computer-aided molecular design

authors

Nascimento ÉCM,Oliva M,Andrés J

doi

10.1007/s10822-018-0114-1

subject

Has Abstract

pub_date

2018-05-01 00:00:00

pages

607-622

issue

5

eissn

0920-654X

issn

1573-4951

pii

10.1007/s10822-018-0114-1

journal_volume

32

pub_type

杂志文章

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