Roles of hybrid donepezil scaffolds as potent human acetylcholinesterase inhibitors using in silico interaction analysis, drug-likeness, and pharmacokinetics prediction

Acetylcholinesterase (AChE) is currently one of the potent targets for the treatment of Alzheimer's disease (AD). The discovery of promising new AChE inhibitors using a hybridisation method is considered as one of the effective strategies to overcome AD. In this study, potent hybrid donepezils previously reported as AChE in-hibitors were investigated to gain an insight into the key binding interaction of their scaffolds, using molecular docking, molecular dynamics simulations and quantum chemical calculations. The results indicated that the key interactions found in both donepezil and the selected hybrid donepezils were the 7C-7C interaction to Trp86 in the catalytic anionic site (CAS) and Trp286 and Tyr341 in the peripheral anionic site (PAS) in the AChE binding pocket. Moreover, the modification of the scaffolds revealed the adaptation of the orientation in the binding pocket and additional important interactions from the modified scaffold, such as H-bond and H-7C interactions to Asp74, Tyr124 and Tyr337. In addition, the HOMO-LUMO prediction indicated the binding interaction by considering the electron transfer between the hybrid donepezils and key residues, such as Trp86 and Trp286. The bioavailability, drug-likeness and pharmacokinetics predictions confirmed the suitability of the hybrid done-pezils for AD drug development. Most of the selected hybrid donepezils revealed good bioavailability, drug-likeness properties and pharmacokinetics; however, some need improved pharmacokinetic properties. The ob-tained information highlights the significance of the scaffold from the hybridisation method, which will be helpful for AD drug design and development in the future.

Automated summary

This study investigated the key binding interactions of hybrid donepezils for the treatment of Alzheimer's disease (AD) using molecular docking, molecular dynamics simulations, and quantum chemical calculations. The results revealed the important interactions between the hybrid donepezils and key residues in the binding pocket of acetylcholinesterase (AChE). The modification of the scaffolds and HOMO-LUMO predictions provided insights into the electron transfer and adaptation in the binding pocket. The bioavailability, drug-likeness, and pharmacokinetics predictions confirmed the suitability of the hybrid donepezils for AD drug development.