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 inhibitors 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 π-π 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-π 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 donepezils 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 obtained information highlights the significance of the scaffold from the hybridisation method, which will be helpful for AD drug design and development in the future.

Binding interaction of protoberberine alkaloids against acetylcholinesterase (AChE) using molecular dynamics simulations and QM/MM calculations.

Acetylcholinesterase (AChE) plays a vital role in Alzheimer's disease (AD), which is one of the most common causes of dementia. Discovering new effective inhibitors against AChE activity is seen to be one of the effective approaches to reduce the suffering from AD. Protoberberine alkaloids isolated from natural resources have previously been reported as potent AChE inhibitors. In order to gain insights into how these alkaloids could inhibit AChE, berberine, palmatine, and cyclanoline were selected to investigate in terms of binding orientation and their key interactions with AChE using molecular docking and molecular dynamics simulations and quantum chemical calculations. The results revealed that the molecular dynamics structures of palmatine and berberine indicated that their equilibrated structures did not occupy the gorge but they slightly moved away from the catalytic site (CAS). For cyclanoline, the binding mode was quite different from those of donepezil and the other protoberberine alkaloids: it preferred to stay deeper in the CAS site. Interaction energies and residual interaction energies confirmed that the key interactions for palmatine and berberine were π-π interactions with Trp286 and Tyr341 and H-bond interactions with Tyr124. Cyclanoline formed π-π interactions with Trp86 and H-bonds to the amino acids in the CAS site. The results suggested the importance of aromaticity in the core structure and the flexibility of the core structure or the substituents in order to fit into the narrow gorge. The HOMO, LUMO, bioavailability, drug-likeness and pharmacokinetics were also predicted. The results obtained will be useful for further AD drug development.