Biological activity identification of newly synthesized plumbagin‐lipoic acid conjugate: In vitro and in silico analyses of interaction with acetylcholinesterase and butyrylcholinesterase

Abstract Background Identification of novel compounds with inhibitory potential against cholinesterases (ChEs) such as acetylcholinesterase (AChE) and butrylcholinesterase (BChE) is considered important strategy to overcome Alzheimer’s disease (AD). The ratio of major globular tetrameric form of AChE (G4) to the minor lower species (G1; monomers and G2; dimers) is decreased in the AD brain. Also, in recent time, the involvement of BChE in progression of AD is recognized. Hence, it is imperative to understand the inhibitory potential of any new compound against BChE and various globular forms of AChE to identify as lead molecule to further explored for AD treatment. Keeping this view, plumbagin (PLU) and lipoic acid (LA) conjugate was synthesized and characterized for its inhibition against AChE and BChE. Further in silico analysis was carried out to get an insight into the interaction of PLU‐LA with the AChE and BChE. Method Newly synthesized PLU‐LA conjugate by esterification reaction was characterized by nuclear magnetic resonance spectroscopy (NMR) and mass spectroscopy (MS). The synthesized PLU‐LA was studied for the inhibition against BChE and different molecular forms of AChE. Kinetic analysis was carried out to determine the type of inhibition and inhibitor constant. In silico analysis such as molecular docking and molecular dynamics simulation was carried out using AutoDock and Desmond, respectively. Result PLU‐LA synthesized was confirmed by NMR and MS analysis. PLU‐LA inhibited the different molecular forms (G2 and G4) of AChE at micromolar concentration. Kinetic analysis revealed the type of inhibition with low Ki value. Molecular docking analysis revealed the orientation of PLU‐LA at the active site of human AChE and BChE forming interaction with catalytic site amino acid. Molecular dynamics simulation confirmed the stable binding of PLU‐LA with ChEs. Conclusion PLU‐LA was synthesized and it’s inhibition against ChEs (AChE and BChE) is understood. In silico analysis highlighted the interaction of PLU‐LA within the active site gorge of the ChEs.