Molecular docking and 3D-QSAR studies of 2-substituted 1-indanone derivatives as acetylcholinesterase inhibitors

Aim:To explore the binding mode of 2-substituted 1-indanone derivatives withacetylcholinesterase (AChE) and provide hints for the future design of new de-rivatives with higher potency and specificity.Methods:The GOLD-docking con-formations of the compounds in the active site of the enzyme were used in subse-quent studies.The highly reliable and predictive three-dimensional quantitativestructure-activity relationship (3D-QSAR) models were achieved by comparativemolecular field analysis (CoMFA) and comparative molecular similarity analysis(CoMSIA) methods.The predictive capabilities of the models were validated byan external test set.Moreover,the stabilities of the 3D-QSAR models were veri-fied by the leave-4-out cross-validation method.Results:The CoMFA andCoMSIA models were constructed successfully with a good cross-validated coef-ficient (q~2) and a non-cross-validated coefficient (r~2).The q~2 and r~2 obtained fromthe leave-1-out cross validation method were 0.784 and 0.974 in the CoMFA modeland 0.736 and 0.947 in the CoMSIA model,respectively.The coefficient isocontourmaps obtained from these models were compatible with the geometrical and physi-cochemical properties of AChE.Conclusion:The contour map demonstrated thatthe binding affinity could be enhanced when the small protonated nitrogen moi-ety was replaced by a more hydrophobic and bulky group with a highly partialpositive charge.The present study provides a better understanding of the inter-action between the inhibitors and AChE,which is helpful for the discovery of newcompounds with more potency and selective activity.