Identification of imidazole-based small molecules to combat cognitive disability caused by Alzheimer’s disease: A molecular docking and MD simulations based approach

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is the primary cause of dementia. It is characterised by the gradual loss of brain cells, which results in memory loss and cognitive dysfunction. One of the hallmarks of AD is an abnormally upregulated glutaminyl-peptide cyclotransferase (QPCT or QC) enzyme. Not only AD, but QC has also been implicated with pathological conditions like Huntington's disease (HD), melanomas, carcinomas, atherosclerosis, and septic arthritis. Therefore, the inhibition of QC emerged as a potential strategy for preventing multiple pathological conditions. Considering this, we screened a library of 153,536 imidazole-based compounds against a doubly mutant (Y115E-Y117E) QC target. Molecular docking based virtual screening and absorption, distribution, metabolism, excretion/toxicity (ADME/T) predictions identified five compounds, namely 118981836, 136459842, 139388116, 139388226, and 139958725. Furthermore, molecular dynamics (MD) simulations of 500 ns were conducted to investigate the behaviour of the identified compounds with the target receptor. The results were compared to the co-ligand by analysing RMSD, RMSF, and SASA parameters. To our knowledge, this is the first computational study that employed a protein with double mutation to identify new imidazole-based QC-inhibitors.