Conformational Analysis and Parallel QM/MM X‑ray Refinement of Protein Bound Anti-Alzheimer Drug Donepezil
- Publication date
- 2013
- Publisher
Abstract
The
recognition and association of donepezil with acetylcholinesterase
(AChE) has been extensively studied in the past several decades because
of the former’s use as a palliative treatment for mild Alzheimer
disease. Herein, we examine the conformational properties of donepezil
and we re-examine the donepezil-AChE crystal structure using combined
quantum mechanical/molecular mechanical (QM/MM) X-ray refinement tools.
Donepezil’s conformational energy surface was explored using
the M06 suite of density functionals and with the MP2/complete basis
set (CBS) method using the aug-cc-pVXZ (<i>X</i> = D and
T) basis sets. The donepezil-AChE complex (PDB 1EVE) was
also rerefined through a parallel QM/MM X-ray refinement approach
based on an in-house ab initio code QUICK, which uses
the message passing interface (MPI) in a distributed SCF algorithm
to accelerate the calculation via parallelization. In the QM/MM rerefined
donepezil structure, coordinate errors that previously existed in
the PDB deposited geometry were improved leading to an improvement
of the modeling of the interaction between donepezil and the aromatic
side chains located in the AChE active site gorge. As a result of
the rerefinement there was a 93% reduction in the donepezil conformational
strain
energy versus the original PDB structure. The results of the present
effort offer further detailed structural and biochemical inhibitor-AChE
information for the continued development of more effective and palliative
treatments of Alzheimer disease