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Ligand-based and energy-optimized structure-based approaches were considered to obtain excellent candidates as AChE inhibitors. The known AChE inhibitors were utilized to develop a pharmacophore hypothesis, HPRRR and X-ray crystallographic structures of AChE were used to produce three e-pharmacophore hypotheses viz. AHHRR, AHRR, and DHRR. Based on in silico approaches, we came across eight structurally diverse hits as non-competitive AChE inhibitors with good ADME properties. The best four hits, ZINC20592007, ZINC05354646, ZINC20649934, and ZINC39154782 were non-toxic, neuroprotective, and were selective AChE inhibitors (IC50 values 482 ± 1.88 nM, 580 ± 1.63 nM, 854 ± 2.65 nM, and 636 ± 1.79 nM respectively). The hits showed non-competitive inhibition of AChE at PAS site with attractive Ki values (0.21 ± 0.027 μM, 0.27 ± 0.064 μM, 0.3 ± 0.018 μM, and 0.28 ± 0.032 μM for ZINC20592007, ZINC05354646, ZINC20649934, and ZINC39154782 respectively), and increased the cholinergic activity as well as inhibited Aβ aggregation.

Multiple 3D-QSAR modeling, e-pharmacophore, molecular docking, and in vitro study to explore novel AChE inhibitors