Microscopic binding of butyrylcholinesterase with quinazolinimine derivatives and the structure–activity correlation

Theoretical Chemistry Accounts (Impact Factor: 2.14). 01/2011; 130(1):69-82. DOI: 10.1007/s00214-011-0965-1

ABSTRACT Butyrylcholinesterase (BChE) is not only an important protein for development of anti-cocaine medication but also an established
drug target to develop new treatment for Alzheimer’s disease (AD). The molecular basis of interaction of a new series of quinazolinimine
derivatives as BChE inhibitors has been studied by molecular docking and molecular dynamics (MD) simulations. The molecular
docking and MD simulations revealed that all of these inhibitors bind with BChE in similar binding mode. Based on the similar
binding mode, we have carried out three-dimensional quantitative structure–activity relationship (3D-QSAR) studies on these
inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA),
to understand the structure–activity correlation of this series of inhibitors and to develop predictive models that could
be used in the design of new inhibitors of BChE. The study has resulted in satisfactory 3D-QSAR models. We have also developed
ligand-based 3D-QSAR models. The contour maps obtained from the 3D-QSAR models in combination with the simulated binding structures
help to better interpret the structure–activity relationship and is consistent with available experimental activity data.
The satisfactory 3D-QSAR models strongly suggest that the determined BChE-inhibitor binding modes are reasonable. The identified
binding modes and developed 3D-QSAR models for these BChE inhibitors are expected to be valuable for rational design of new
BChE inhibitors that may be valuable in the treatment of Alzheimer’s disease.

KeywordsButyrylcholinesterase–Inhibitor–Binding mode–Modeling