Identification of novel acetylcholinesterase inhibitors designed by pharmacophore-based virtual screening, molecular docking and bioassay

Abstract

In this study, pharmacophore based 3D QSAR models for human acetylcholinesterase (AChE) inhibitors were generated, with good significance, statistical values (r2training = 0.73) and predictability (q2training = 0.67). It was further validated by three methods (Fischer’s test, decoy set and Güner-Henry scoring method) to show that the models can be used to predict the biological activities of compounds without costly and time-consuming synthesis. The criteria for virtual screening were also validated by testing the selective AChE inhibitors. Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed a novel and selective AChE inhibitor. Thus, the findings reported herein may provide a new strategy for the discovery of selective AChE inhibitors. The IC50 value of compounds 5c and 6a presented selective inhibition of AChE without inhibiting butyrylcholinesterase (BChE) at uM level. Molecular docking studies were performed to explain the potent AChE inhibition of the target compounds studies to explain high affinity.

In silico and in vitro studies of two non‐imidazole multiple targeting agents at histamine H3 receptors and cholinesterase enzymes

“…For example, amino acids Trp 82 , Tyr 332 , and His 438 from BuChE are equivalent to Trp 86 , Tyr 341 , and His 447 from AChE in terms of interactions with the ligand. The results of molecular docking studies are in line with formerly published findings (Bajda et al, ; Darras et al, ; Jang et al, ; Lazewska et al, ; Morini et al, ). In addition, the results of binding affinity prediction for the complexes of ligand‐cholinesterase are consistent with the experimentally determined anticholinesterase activity of compounds 3 and 4 .…”

Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders

“…The GH score ranges between 0 and 1 and indicates null and ideal models, respectively. Pharmacophore model with GH score higher than 0.70 is considered as valid model for virtual screening of large databases [ 31 , 32 ]. The enrichment factor (EF) determines the specificity and selectivity of the model to identify active compounds during the screening of decoy test set.…”

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

“…A number of studies dealing with the application of the parallel strategy in the search of novel hits have been reported in the last years [ 118 , 119 , 120 , 121 ]. An illustrative example is the work by Vucicevic et al [ 119 ], who reported the identification of compounds with anticancer potential effects through a parallel LB and SB screening protocol ( Figure 4 A).…”