In Silico ADME and QSAR Studies on a Set of Coumarin Derivatives As Acetylcholinesterase Inhibitors Against Alzheimer’s Disease: CoMFA, CoMSIA, Topomer CoMFA, and HQSAR

Background: Alzheimer’s disease (AD) is increasingly being recognized as one of the lethal diseases in older people. Acetylcholinesterase (AChE) has proven to be the most promising target in AD, used for designing drugs against AD. Methods: In silico studies, 2D- or 3D-QSAR like hologram QSAR (HQSAR), Topomer comparative molecular field analysis (Topomer CoMFA), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) methods were used to generate QSAR models for acetylcholinesterase inhibitors. Results: Acetylcholinesterase inhibitors used for the present study contain a series of 7- hydroxycoumarin derivatives connected by piperidine, piperazine, tacrine, triazole, or benzyl fragments through alkyl or amide spacer training set compounds were used to generate best model with a HQSAR q2 value of 0.916 and r2 value of 0.940; a Topomer CoMFA q2 value of 0.907 and r2 value of 0.959, CoMFA q2 value of 0.880 and r2 value of 0.960; and a CoMSIA q2 value of 0.865 and r2 value of 0.941. In addition, contour plots obtained from QSAR models suggested the significant regions that influenced the AChE inhibitory activity. Conclusion: In light of these results, this study provides knowledge about the structural requirements for the development of more active acetylcholinesterase inhibitors. In addition, the predicted ADME profile helps us to find CNS active molecules, the obtained prediction compared with well-known AChE inhibitors viz., ensaculin, tacrine, galantamine, rivastigmine, and donepezil. Based on the knowledge obtained from these studies, the hybridization approach is one of the best ways to find lead compounds and these findings can be useful in the treatment of Alzheimer's disease.