Molecular engineering and activity improvement of acetylcholinesterase inhibitors: Insights from 3D-QSAR, docking, and molecular dynamics simulation studies.

The carbamate molecule rivastigmine was found to possess promising anti-acetylcholinesterase activity, enabling to target and occupy choline binding sites, and as a result, widely used to improve the treatment of Alzheimer's disease (AD). Higher dose of rivastigmine indicates rapid onset but more adverse effects, such as the large fluctuations in plasma concentration level and frequent incidence of gastrointestinal side effect. To solve the dilemma, we developed a three-dimensional quantitative structure-activity relationship (3D-QSAR), docking and molecular dynamics (MD) simulation strategy to construct a dismountable nanoplatform of inhibitor engineering, verification and application for improving the inhibitory activity per unit concentration. With the aid of 3D-QSAR method, we constructed a model by using 25 molecules reported, and verified well the rationality of these QSAR models by non-cross validation coefficient (r2 = 0.902). Docking and MD results show that rivastigmine, as a control, does target exactly the binding sites of acetylcholinesterase, those already observed experimentally, in turn, confirming the reliability of the present 3D-QSAR results. The method suggests that groups with electron-donating chemical property can improve the inhibitory activity, and screens out two novel inhibitors L-1 and L-2 with more activity from database (about 8000 compounds). Moreover, L-1 and L-2 not only target exactly the same binding sites of acetylcholinesterase as the rivastigmine does, but also hold stronger binding energy, showing a more powerful inhibitory ability. More broadly, this work showcases an approach in the engineering of carbamate inhibitors to enhance their inhibitory activity using electron-donating groups, which simplifies the design process of complex bioactive molecules. The 3D-quantitative structure-activity relationship (3D-QSAR) was used to find and screen the novel inhibitor of anti-acetylcholinesterase (AChE) activity, which was validated by its excellent r2 and q2 values, as well as by the available experiment results of Montanari et al. The docking and molecular dynamic simulation further provided mechanical details of AChE-inhibitor interaction. [Display omitted] • The integrated 3D-QSAR, Docking and MD approach identified potential inhibitors against Alzheimer's disease. • The inhibitory activity can be improved by Substituting the R groups with electron-donating property. • The approach would be of great value for optimizing bioactivity and studying the mechanisms of bioactive molecules. [ABSTRACT FROM AUTHOR]