Discovery of drug-like acetylcholinesterase inhibitors by rapid virtual screening of a 6.9 million compound database

التفاصيل البيبلوغرافية
العنوان: Discovery of drug-like acetylcholinesterase inhibitors by rapid virtual screening of a 6.9 million compound database
المؤلفون: Ross P. McGeary, Charlotte Courageux, José A. Dias, Jia Hui Ng, Alexandre Igert, Benjamin P. Ross, Jared A. Miles, Xavier Brazzolotto, B. Yogi Sreenivas
المصدر: Chemical biologydrug designREFERENCES. 97(5)
سنة النشر: 2021
مصطلحات موضوعية: Drug, In silico, media_common.quotation_subject, Mixed inhibition, Molecular Dynamics Simulation, computer.software_genre, 01 natural sciences, Biochemistry, Permeability, chemistry.chemical_compound, Alzheimer Disease, Catalytic Domain, Drug Discovery, Animals, Donepezil, Horses, Cholinesterase, media_common, Pharmacology, Virtual screening, Binding Sites, biology, Database, 010405 organic chemistry, Organic Chemistry, Ligand (biochemistry), Acetylcholinesterase, In vitro, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Kinetics, chemistry, Butyrylcholinesterase, Electrophorus, biology.protein, Molecular Medicine, Cholinesterase Inhibitors, computer, Databases, Chemical
الوصف: Cholinesterase inhibitors remain the mainstay of Alzheimer's disease treatment, and the search for new inhibitors with better efficacy and side effect profiles is ongoing. Virtual screening (VS) is a powerful technique for searching large compound databases for potential hits. This study used a sequential VS workflow combining ligand-based VS, molecular docking and physicochemical filtering to screen for central nervous system (CNS) drug-like acetylcholinesterase inhibitors (AChEIs) amongst the 6.9 million compounds of the CoCoCo database. Eleven in silico hits were initially selected, resulting in the discovery of an AChEI with a Ki of 3.2 µM. In vitro kinetics and in silico molecular dynamics experiments informed the selection of an additional seven analogues. This led to the discovery of two further AChEIs, with Ki values of 2.9 µM and 0.65 µM. All three compounds exhibited reversible, mixed inhibition of acetylcholinesterase. Importantly, the in silico physicochemical filter facilitated the discovery of CNS drug-like compounds, such that all three inhibitors displayed high in vitro blood-brain barrier model permeability.
تدمد: 1747-0285
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::37a59cb21fe096d1aa8d76fa0dd74606
https://pubmed.ncbi.nlm.nih.gov/33455074
Rights: CLOSED
رقم الانضمام: edsair.doi.dedup.....37a59cb21fe096d1aa8d76fa0dd74606
قاعدة البيانات: OpenAIRE