Discovery of novel fatty acid amide hydrolase (FAAH) inhibitors as anti-alzheimer agents via in-silico-based drug design, virtual screening, molecular docking, molecular dynamics simulation, DFT, and non-clinical studies

To identify some novel fatty acid hydrolase (FAAH) inhibitors that may contribute to the treatment of Alzheimer's disease (AD). In-silico pharmacophore modelling including ligand-based pharmacophore modelling, virtual screening, molecular docking, molecular dynamics modelling, density functional theory and in-silico pharmacokinetics and toxicological studies were employed for the retrieving of novel FAAH inhibitors. Further, these compounds were evaluated for FAAH inhibitory activity using an in vitro enzymatic assay, and later, an in vivo streptozotocin (STZ)-induced AD model was examined in mice. Using an in-silico pharmacophore modelling process with molecular docking, molecular dynamic modelling, density functional theory and in-silico pharmacokinetics and toxicological analysis, three compounds (NCI1697, NCI1001and NCI1041) were retrieved. The in vitro FAAH activity assay kit (Fluorometric) was employed to examine the FAAH inhibitory activity of identified compounds. Further, in in-vivo studies, treatment with these compounds at 2.5 and 5 mg/kg doses orally for 10 days restored the STZ-induced memory deficits in mice, as evident in the radial arm and Morris's water maze assays. Also, these compounds ameliorated oxidative stress profiles and neuroinflammatory biomarkers in mice. Interestingly, STZ-induced disturbance in gene expressions related to AD pathophysiology including endocannabinoid signalling neuroinflammation and neuroimmune signalling were also restored after the treatment. Histopathological findings also confirmed the improvement in the organization of cells and reduction in vacuolation in mice hippocampal tissue in treated mice. The in-silico, in vitro and in-vivo findings collectively indicated that these compounds have impressive FAAH inhibitory activity and may be developed as therapeutic agents in the management of AD. •Fatty acid hydrolase (FAAH) is a key therapeutic target in Alzheimer's disease (AD).•NCI1001, NCI1041, and NCI1697 exhibited impressive FAAH inhibitory activity.•These compounds demonstrated good pharmacokinetic profile in in silico ADMET analysis.•FAAH inhibitors could be effective in the management of AD.