Fig 1.
The design of new analogues based on the potent, first generation molecule, donepezil.
Here, D1 was designed from donepezil, while others (D2 to D10) are based on the basic structure of D1.
Fig 2.
Most stable optimized structures of all designed analogues along with their parent molecule, donepezil.
All analogues were optimized in the gas phase at B3LYP/SDD level in Gaussian 09.
Table 1.
The stoichiometry, electronic energy, enthalpy, Gibbs free energy (in Hartree), and dipole moment (Debye) of donepezil and its designed analogues.
Fig 3.
Molecular orbital distribution plots of HOMO and LUMO in the ground state of D9 analogue and donepezil at DFT/SDD level of theory in the gas phase.
Table 2.
Energy of HOMOs, LUMO, gap, hardness and softness (all units are in Hartree) of the donepezil and its designed analogues.
Fig 4.
Predicted pose from molecular docking by Autodock Vina.
Here, the stick representations of ligands denote the superimposed view of docked (pink) and co-crystallized ligand (green).
Fig 5.
Predicted pose from the docking analysis showed the binding orientation map of important amino acids for analogue D9, showing hydrogen bond interaction (green color), including π–π stacking (pink color).
Table 3.
Binding affinity (kcal/mol) and nonbonding interactions of donepezil and its designed analogues.
Fig 6.
The time series of the RMSD of backbone atoms (C, Cα, and N) for a) protein and b) ligand for each docked complex. Here, red and blue lines denote donepezil and D9 complex respectively.
Fig 7.
The structural changes of protein by means of a) solvent accessible surface area (SASA), b) radius of gyration, and c) root means square fluctuations (RMSF) analysis. Here, red and blue lines denote donepezil and D9 complex, respectively.
Fig 8.
Total number of hydrogen bonds formed a) within the protein and b) between the protein and ligand in complex state during the simulation. Here, red and blue lines denote donepezil and D9 complex, respectively.
Fig 9.
Conformational changes of the D9-AChE complex.
Here, the stick model of the ligand in blue color represents the starting conformation of the complex, while the green color represents the conformation of last step in the 25 ns long MD simulation.
Fig 10.
Binding affinities of designed ligands and standard inhibitor, obtained from ensemble based docking analysis.
Here, binding affinities of D8, D9, D10, and donepezil against multiple AChE conformers from a) protein data bank and b) 25 ns MD simulation.
Table 4.
Ensemble based docking against all crystal structures of AChE.
Table 5.
Binding affinity values of donepezil, D8, D9, and D10 docked against multiple AChE conformers generated by 25 ns MD simulation.
Table 6.
Nonbonding interactions of the best docked complexes obtained from ensemble based docking analysis.
Table 7.
Selected pharmacokinetic parameters of donepezil and its designed analogues.