Virtual Screening of Acetylcholinesterase Inhibitors Using the Lipinski’s Rule of Five and ZINC Databank

Abstract

Alzheimer's disease (AD) is a progressive and neurodegenerative pathology that can affect people over 65 years of age. It causes several complications, such as behavioral changes, language deficits, depression, and memory impairments. One of the methods used to treat AD is the increase of acetylcholine (ACh) in the brain by using acetylcholinesterase inhibitors (AChEIs). In this study, we used the ZINC databank and the Lipinski's rule of five to perform a virtual screening and a molecular docking (using Auto Dock Vina 1.1.1) aiming to select possible compounds that have quaternary ammonium atom able to inhibit acetylcholinesterase (AChE) activity. The molecules were obtained by screening and further in vitro assays were performed to analyze the most potent inhibitors through the IC50 value and also to describe the interaction models between inhibitors and enzyme by molecular docking. The results showed that compound D inhibited AChE activity from different vertebrate sources and butyrylcholinesterase (BChE) from Equus ferus (EfBChE), with IC50 ranging from 1.69 ± 0.46 to 5.64 ± 2.47 µM. Compound D interacted with the peripheral anionic subsite in both enzymes, blocking substrate entrance to the active site. In contrast, compound C had higher specificity as inhibitor of EfBChE. In conclusion, the screening was effective in finding inhibitors of AChE and BuChE from different organisms.

Isopropyl Caffeate: A Caffeic Acid Derivative—Antioxidant Potential and Toxicity

“…It is worth noting that no chemical is free of toxicity; the study of toxic effects is as necessary as knowledge concerning side effects, interactions, contraindications, and mutagenicity [ 10 – 12 ]. Substance toxicity is often related to the formation of free radicals, which cause oxidative stress and are responsible for a large number of diseases [ 13 – 15 ].…”

An Integrated Computational Approach for Plant-Based Protein Tyrosine Phosphatase Non-Receptor Type 1 Inhibitors

“…Several filters were selected before screening by ZINCpharmer. These criteria dictated that the molecular mass of the compound should be less than 500 Daltons, the number of rotatable bonds should be less than 10 [ 38 ], the maximum hits per configuration should be one, the maximum hits per molecule should be one and the maximum root-mean-square deviation (RMSD) value for screened hits should be 1.5. The identified pharmacophore fit compounds from the databases were required to be drug-like.…”

Systematic Understanding of Mechanisms of a Chinese Herbal Formula in Treatment of Metabolic Syndrome by an Integrated Pharmacology Approach

“…Additionally, the drug-likeness analysis was also performed to evaluate the oral drug-like property of chemical ingredients in WDD using the Lipinski rule of five, that is, molecular weight lower than 500 Da, number of H-bond donors (a don) less than five, number of H-bond acceptors (a_acc) less than 10, number of rotatable bonds (b_rotN) lower than 10 and octanol-water partition coefficient (logP( o / w )) lower than five, is of importance for the screening of drugs with pharmacological activity [21,22]. The drug-like property descriptors of WDD ingredients were listed in Table 2.…”