The Interaction of a Novel Drug with β-secretase-1 and Acetylcholinesterase: A Computational Investigation from Both Dynamics and Thermodynamics Viewpoints

Inhibition of glycogen synthase kinase-3 (GSK-3), β-secretase 1 (BACE-1), and acetylcholinesterase (AChE) could block one of the initial pathological events of Alzheimer’s disease (AD). Recently, a new class of drugs has been developed with significant potential for GSK-3 inhibition. In this research, to the discovery of the new ligand as the potential multi-target drug with effective anti-Alzheimer’s action a detailed computational investigation has been carried out on the effect of one of the most important drugs of such class on BACE-1 and AChE enzymes. The results of the binding free energies (∆GBind) showed that the binding of this drug to AChE (-67.77 kJ/mol) is thermodynamically more favorable than BACE-1 (-22.35 kJ/mol). Examination of dynamic properties such as the root mean square fluctuation (RMSF) and the propensity for the secondary structure demonstrated that due to the decrease in the β-sheet and β-bridge content as well as the increase in the random coil content of BACE-1 in the presence of the drug, this enzyme was completely more flexible than AChE. The free-energy landscape (FEL) based on the first and second motion modes (PC1 and PC2) indicated that the large concerted motions of BACE-1 found in the simulations were particularly more sensitive to this drug than AChE.