Molecular docking studies on the alkaloid (+)-buxabenzamidienine from Buxus sempervirens L. with anticholinesterase effect

Alzheimer's disease (AD), the most common form of dementia, is a neurodegenerative disease characterized by progressive cognitive deterioration together with declining activities of daily living and neuropsychiatric symptoms or behavioural changes. AD is also characterized by a low concentration of acetylcholine (ACh) in hippocampus and cortex. The acetylcholinesterase (AChE, EC 3.1.1.7) is one of the most important enzymes in human and many different vertebrates. The fundamental role of the enzymes AChE and butyrylcholinesterase (BChE, EC 3.1.1.8) at cholinergic synapses is to terminate neurotransmission by rapid hydrolysis of the substrate, acetylcholine (ACh). The oldest, on which the most currently available drug therapies are based, is known as the „cholinergic hypothesis“ and suggests that AD begins as a deficiency in the production of the neurotransmitter acetylcholine. Therefore, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors have gained a great popularity for the treatment of AD. In this work, some theoretical (quantum mechanical and docking) calculations on the alkaloid named (+)-buxabenzamidienine (1) isolated from Buxus sempervirens L. (Buxaceae) was performed to explain their interactions with different AChE (electric eel and human) and BChE (horse and human). DFT calculations of 1 have been performed at the B3LYP/6–31G** level using the program Spartan™. Its HOMO and LUMO energy levels have been calculated and presented here. Some bioinformatic studies have been done to compare the AChE between electric eel and human to rationalize the docking using both the enzymes. Docking studies exhibited that compound 1 in hAChE interact with the acyl-binding pocket of the active site gorge, including several other hydrophobic interactions. Mostly the interactions of 1 have been compared with human cholinesterases to get insight of the interfaces of the drug and human being.

Acknowledgements: Authors I.O., S.A., M.K., and B.Ş. acknowledge the financial grant for this work provided by The Scientific and Technological Research Council of Turkey (TUBITAK) through the research project coded as 104T492. Authors M.T.H.K. and I.S. acknowledge the financial support from University of Tromsø, Norway