In-silico docking and virtual screening of natural products as possible BACE۱ inhibitors: a new hope for treatment of Alzheimer’s disease?

The most common cause of dementia and the fifth most prevalent cause of mortality in people over ۶۵ is Alzheimer’s disease (Wung, ۲۰۲۰). A di↵erent pharmacological target for treating AD is needed due to the ongoing failure of present therapies. BACE۱ is a widely recognized prospective therapeutic target for Alzheimer’s disease because it catalyzes the rate-determining step in the production of A peptides (Kumar et al., ۲۰۲۰). COCONUT database (Collection of Open Natural Products database) was screened for creating a library of natural products with the following filters: ۱. molecular weight between ۴۰۰-۶۰۰ ۲. Lipinski’s role of five. One hundred best hits were downloaded as a library. We used the protein ۳D structure of BACE۱ (PDB ID: ۷MYI; X-Ray; Chain A/B; ۱.۲۵ ˚A) for docking. All the ligands and the ۳D structure of the BACE۱ were then prepared using the Schro¨dinger suite (Maestro ۱۱.۵) Ligprep module and ProPrep wizard, respectively. Ligand docking in the module GLIDE of the Schro¨dinger suite was used for the evaluation of the interaction between ligands and chain A of the target protein (opls۲۰۰۵ forcefield). Best ligands according to glide E-model and docking score were evaluated for pharmacokinetic properties predictions by Swiss ADMET, pkCSM, and ADMETlab ۲.۰. Molecular docking analyses of our natural products library found promising ligands that had excellent protein-ligand interactions with BACE۱ and reasonable docking scores (CNP۰۲۷۸۶۵۲, CNP۰۰۱۴۲۳۰, CNP۰۳۸۵۷۵۴, CNP۰۱۹۴۶۱۶, CNP۰۱۷۸۹۷۲, CNP۰۲۵۱۰۹۶, CNP۰۳۹۳۹۵۶ and CNP۰۳۶۶۰۱۶). Some of these ligands displayed acceptable pharmacokinetic and physicochemical characteristics, such as good absorption, distribution, metabolism, and excretion (ADMET). BACE۱ appears to be a promising target for the development of novel medications. Future in-vivo and in-vitro research is necessary to provide additional information about this target, nevertheless.

کلیدواژه ها:

Alzheimer ، In-Silico ، Drug design ، Natural Products