Polypharmacological and Computational Approaches to Establish HDAC Inhibitors in the Treatment of Alzheimer

Alzheimer's is a progressive cognitive condition with significant loss of neuronal functions, formation of amyloid plaque, and neurofibrillary tangles. Gamma secretase, acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and GSK-3beta enzymes regulated the progression of Alzheimer's disease. HDAC6 enzyme also improved the axonal activity linked to Alzheimer's disease. In this manuscript, we repurposed the role of HDAC inhibitors [HDACi(s)] towards the treatment of Alzheimer's disease by inhibiting gamma-secretase (6LQG), AChE (7AIT), BuChE (6QAE), and GSK-3beta (3GB2) enzymes. Here, we considered 60 HDACI and then filtered out 16 molecules using SWISS-ADME parameters. Docking score of Analog 45 and Analog 57 against 6LQG, 7AIT, 6QAE and 3GB2 were (-) 8.1 kcal/mol, (-) 10.5 kcal/mol, (-) 9.1 kcal/mol, (-) 7.3 kcal/mol and (-) 8.2 kcal/mol, (-) 11.5 kcal/mol, (-) 9.5 kcal/mol, (-) 8.0 kcal/mol respectively; whereas Rivastigmine showed docking score of (-) 5.3 kcal/mol, (-) 8.0 kcal/mol, (-) 7.2 kcal/mol, (-) 6.1 kcal/mol. Based on docking score, we selected (E)-N-(2-amino-4-fluorophenyl)-3-(1-cinnamyl-1H-1,2,3-triazol-4-yl)acrylamide (Analog 45), N-methyl-4-((3-(pyrrolidin-1-ylmethyl)-1H-indol-1-yl)methyl)benzamide (Analog 57) and Rivastigmine for further studies. Then, we performed OSIRIS-MOLINPIRATION profiling to observe the most effective and low-toxic molecule. Analog 57 passed the criteria. Finally, we performed FMO and EPS analyses using (B3LYP) 6-311G+(d,p) to observe the electronic nature of the molecule. HOMO orbital localized on the indole nucleus and LUMO orbital localized on N-methyl benzamide group.EPS analysis data showed that nitrogen atoms of pyrrolidine and indole [3-[(pyrrolidin-1-yl)methyl]-1H-indole of this nucleus] and also O=C-N of benzamide nucleus were feasible for the electrophilic attack. In the same manner, benzene of the indole ring and terminal methyl group of benzamide were suitable for nucleophilic attack. Finally, we stated that N-methyl-4-((3-(pyrrolidin-1-ylmethyl)-1H-indol-1-yl)methyl) benzamide is the best molecule repurposed for the management of Alzheimer's.