Patil_2021_In.Silico.Pharmacol_9_51

A critical approach for target identification to detect the significant molecular mechanism of lead molecules via computational methods combined with in vitro procedures defines the modern strategy to combat untreatable diseases. Hence, the present investigation dealt to determine the effect of Erythrina variegata L. bark extract/fraction(s) over acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity followed by target identification and docking analysis of prime phytoconstituents. The in vitro AChE and BChE enzyme inhibitory assay were performed. Phytoconstituents from E. variegata were screened for carcinogenicity and mutagenicity and predicted for their possible targets leading to the identification of two known targets, i.e. AChE and BChE. The alkaloids with non-carcinogenic and non-mutagenic properties were studied for their main moiety responsible for the inhibitory activity. The protein models were checked in ERRAT for their quality and the homology model was created using Modeller9.10v to fill missing amino acid residues. The docking study predicted the binding affinity of bioactive molecules with identified targets using AutoDock 4.2. Molecular dynamics (MD) simulations for top hits were performed by Schrodinger Desmond 6.1v software. Chloroform fraction showed potent inhibition of AChE and BChE with IC(50) value of 38.03 +/- 1.987 microg/mL and 20.67 +/- 2.794 microg/mL, respectively. Among all the six major bioactive compounds, Erysotine and Erythraline scored the highest binding affinity with AChE and Erysodine with BChE. MD simulation for 20 ns production run demonstrated Erysotine and Erysodine stable interaction with Arg49 of AChE and Lys427 of BChE, respectively. The current data provide enough shreds of evidence supporting the utilization of indolo [7a,1-a] isoquinoline derivatives for the identification of a new drug molecule in the management of Alzheimer's disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00110-0.