Özet:
Alzheimer's disease (AD) is a central nervous system chronic condition that causes
a decrease in cognitive control and language capacity. AD is associated with
cholinergic deficiency, and various cholinesterase inhibitors, including naturally
derived inhibitors, synthetic analogs, and hybrids have been developed to treat
AD. The drugs available for AD are currently mainly cholinesterase inhibitors.
However, the efficacy of these drugs was limited, as they can cause adverse side
effects and are unable to stop the progression disease entirely.
Initially, in the current study, 7922 small compounds were retrieved from NIH
Chemical Genomics Center (NCGC) pharmaceutical collection (NPC) library to be
screened through QSAR model developed from targets against AD. The molecules
with higher AD therapeutic activity values (>0.75) were then used in the 26
different toxicity-QSAR models. Binary QSAR models resulted in 10 hits that have
high AD therapeutic activity and no toxicity. The selected hits were then screened
against acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) targets
using standard precision docking (SP), induce fit docking (IFD) and quantum
mechanics-polarized ligand docking (QPLD). Top IFD docking poses for five
compounds were used in, initially, short (50 ns), and then long (100 ns) molecular
dynamics (MD) simulations. Molecular Mechanics/Generalized Born Surface Area
(MM/GBSA) binding free energy calculations were performed for the five top
compounds. A similar protocol was also applied for three of the known AChE and
BuChE inhibitors. Finally, based on MM/GBSA scores and their corresponding
docking scores, three compounds were ordered, and their in vitro tests were
performed. All compounds showed nM-level inhibition for both AChE and BuChE
targets. The outcomes of this study may open a new perspective for the
development of novel drugs with reduced toxicity and preserved pharmacological
activity against AD.
