molecular docking and plif studies of novel tacrine-naphtoquinone hybrids based on multi-target-directed ligand approach for alzheimer’s disease

Background: alzheimer’s disease (ad), the most typical type of dementia and memory loss, is a complicated and progressive neu- rodegenerative disorder. due to the multi-factorial etiology of ad, the multi-target-directed ligand (mtdl) approach can be a poten- tial method in seeking new drug candidates for this disease. methods: in this study, over 200 tacrine-naphtoquinone hybrids have been designed and their drug-likeness, molecular docking, and descriptor analysis were conducted to find out a drug candidate with less toxicity and better binding affinity than tacrine. the docking analysis was conducted using human acetylcholineesterase (1acj), human butyrylcholineesterase (4bds), and β-secretase (bace1) (1w51) enzymes using autodock 4.2 and vina. results: promising results were obtained on the types of interactions. based on molecular docking on 3 targets as well as protein ligand interaction fingerprint (plif) studies, the compounds with better results were introduced as good candidates for synthesis. the validity of docking protocols was confirmed using a set of familiar active ligands and decoys on these targets by means of 2 known statistical metrics such as the receiver-operating characteristic (roc) and enrichment factor (ef). conclusion: structure activity relationship (sar) studies, in these class of compounds, show that the hydroxyethylamine, as a linker, is an essential group to improving binding site to ache and bace-1 targets.