Ligand-based pharmacophore modeling to identify plant-derived acetylcholinesterase inhibitor natural compounds in Alzheimer’s disease

Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by decreased cognitive function in patients due to forming Aβ peptides and neurofibrillary tangles (NFT) in the brain. Therefore, the need to develop new treatments can reduce this risk. Acetylcholinesterase is one of the targets used in the design of new drugs for the treatment of AD. The researchers obtain new inhibitory ligands based on natural compounds from various medicinal plants, such as the family of Asteroideace, Malvacea, Zingbracea, Hypericacea, and Ebenacea, for treating Alzheimer’s disease.  Methods: After selecting the reference compound of the enzyme acetylcholinesterase inhibitor with the help of bioinformatics tools such as pharmit and ZINCPHARMER for virtual search through the structural and pharmacologic properties of the reference inhibitor compound, several thousand natural structures of several serious ligands were obtained. Then, the ligands were compared by examining the docking process with the acetylcholinesterase enzyme, and their interactions were visualized with the help of Discovery Studio. Then, the top selected ligands in terms of toxicity, allergy, toxicity, and ADME prediction were evaluated with tools such as molsoft, PKCSM, ADMEtlab2.0, Swiss MADE. Results: The results revealed that these obtained ligands, like donepezil, have the ability of favorable interactions with different amino acids, the crucial of which are HIS381, TRP385, and GLN527 of AChE, and they all fall in the active site or binding pocket of the active site. The present docking supports this hypothesis that these compounds are possible and valuable small molecule ligands for targeting/inhibiting acetylcholinesterases. Indicatively, according to the binding free energy calculation results, it can be concluded that these ligands can compete with donepezil and affect the formation of acetylcholinesterase complexes. Cholinesterase/donepezil can have an excellent competitive inhibitory effect on it. Conclusion: On the other hand, the study on the designed ligands showed that with favorable interactions and lower binding energy, they form more stable complexes with acetylcholinesterase and can be proposed as inhibitors competing with donepezil in a bind to this enzyme.