NEUROLOGY AND NEUROBIOLOGY | ISSN 2613-7828 Available online at www.sciencerepository.org Science Repository * Correspondence to: Sidra Batool, Department of Biosciences, COMSATS University, Park Road, Chak Shahzad, 45550, Islamabad, Pakistan; E-mail: sidra.batool@comsats.edu.pk © 2021 Sidra Batool. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository. http://dx.doi.org/10.31487/j.NNB.2021.02.02 Research Article In silico Analysis of Alkaloids for Therapeutic Use in Treatment of Alzheimer's Disease by Targeting Acetylcholinesterase Enzyme Muhammad Sibte Hasan Mahmood 1 , Tiyyaba Furqan 2 , Muaaz Karim 3 and Sidra Batool 2* 1 Medicine Department, Grand River Hospital, Kitchener, Canada 2 Department of Biosciences, COMSATS University, Islamabad, Pakistan 3 Neurology Research Department, Ziauddin University, Karachi, Pakistan A R T I C L E I N F O Article history: Received: 4 May, 2021 Accepted: 14 May, 2021 Published: 28 May, 2021 Keywords: Beta carbolines alkaloids docking acetylcholinesterase inhibitor A B S T R A C T Alzheimer’s is a progressive mental deterioration associated with the degeneration of the cognition activities and memory loss. It is considered to be a multifactorial disease. One of the causes of the Alzheimer’s disease is the low concentration of the neurotransmitter named acetylcholine (ACh) at the synaptic cleft. Thus, inhibitor of Acetylcholinesterase (AChE), an enzyme whose function is to degrade the acetylcholine, is proved to be a promising candidate to treat this disease. Among the inhibitors are the natural alkaloids that also have an inhibitory effect on the AChE. In this study we have focused on the simple derivates of beta carbolime (a group of alkaloids) and studied their interaction with AChE via rigid protein-ligand docking approach. © 2021 Sidra Batool. Hosting by Science Repository. Introduction Alzheimer’s disease is a progressive, age related neurodegenerative disorder that affects nearly 2% of the population of industrialized countries [1]. It is generally diagnosed in individuals above 65 years of age and is the primary cause of the memory loss (dementia) in elderly individuals. Each year 4.6 million new cases of Alzheimer’s disease are reported and according to a report generated by World Health Organization (WHO), by 2040, 71% of the 81.1 million dementia cases will occur in developing countries [2, 3]. Alzheimer’s disease is considered to be a multifactorial disease i.e., having more than one factors contributing to the pathogenesis of the disease. It is caused by the accumulation of amyloid beta. Amyloid beta is a peptide of 36 to 43 amino acids which is formed as a result of the cleavage of amyloid beta precursor protein by beta secretase and gama secretase enzyme [4]. Amyloid beta starts up as a single molecule which initially clusters up to form the plagues. As a result, the connection between the synapses is disrupted which causes the loss of memory and other cognitive abilities [5]. Another factor contributing to Alzheimer’s disease is the low concentration of ACh at the synaptic cleft resulting in the death of the cholinergic neurons which causes the loss of the memory [6]. Acetylcholinesterase (AChE) is an enzyme present in the nervous tissue, muscles and red blood cells that hydrolyze acetylcholine into choline and acetic acid. Thus the inhibition of the acetylcholinesterase enzyme will prevent the breakdown of the acetylcholine present in the nerve cells and will result in the increase of the Ach concentrations thus preventing the Alzheimer’s disease (and memory loss) [7]. The physiological importance of the ACh enhanced the focus on the inhibitors of acetylcholinesterase. Tetrohydroaminoacridine (THA) named as Tacrine or Cognex was the first drug approved by US FDA (Food and Drug administration) in 1993 for the treatment of Alzheimer’s disease. Its use improved the memory and cognitive ability of Alzheimer’s patients but had a lot of side effects including nausea, liver dysfunction, vomiting, diarrhea and dizziness. Another drug Donepezil was approved by FDA in 1996 having more substrate specifity thus minimizing the side effects. Rivastigmine, galantamine, memantine were approved by FDA in 2000, 2001 and 2003 respectively. All of these drugs work by inhibiting acetylcholinesterase thus improving ACh concentration in synaptic cleft and as a result memory and other cognitive abilities are improved [8, 9].