Paper Title
Molecular Docking Studies of Coumarinderivatives as Novel Acetylcholinesterase Inhibitors

Abstract
The inhibitor that can bind to the peripheral anionic site (PAS) and catalytic active site (CAS) of human acetylcholinesterase (hAChE) and human monoamine oxidase type B (hMAO-B) have been targeted as the new potential therapeutic for treatment of Alzheimer’s disease (AD). In the present work, we are interested in designing a new series of the coumarin derivatives to serve as multi-target-directed-ligands (MTDLs) for hAChE/hMAO-B based on molecular docking. The binding energy of coumarin derivatives to hAChE were investigated which confirmed that most of designed compounds showed higher binding interactions than the reference drug (donepezil). Interestingly, all coumarin derivatives exhibited the strong binding interactions to hMAO-B than the reference drug assafinamide. The obtained results indicated that increasing of the aromaticity together with the promising linker hybrid to the coumarin moietyof these novel compounds would influence to their mode of binding. Furthermore, the substituent effect on the coumarin moiety was explored to improve the binding affinity. Among them the para-acetyl substituted group (A7) was identified as the most potent inhibitor to both hAChE and hMAO-B. More importantly, A7 showed the highest binding energies to hAChE due to the hydrophobic interactions and strong hydrogen bondings were formed to key residues in the CAS and PAS. Finally, in silico study was confirmed that all designed compounds fulfilled drug likeliness properties (Lipinski’s rule of five). Therefore, we were expected that these novel coumarin derivatives could be proposed as the potential multifunctional anticholinesterase for AD therapy. Keywords - Alzheimer’s disease, Acetylcholinesterase, Monoamine oxidase, Multi-target-directed-ligands, Coumarin.