The Interaction of a Novel Drug with β-secretase-۱ and Acetylcholinesterase: A Computational Investigation from Both Dynamics and Thermodynamics Viewpoints

Inhibition of glycogen synthase kinase-۳ (GSK-۳), β-secretase ۱ (BACE-۱), 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-۳ 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-۱ and AChE enzymes. The results of the binding free energies (∆GBind) showed that the binding of this drug to AChE (-۶۷.۷۷ kJ/mol) is thermodynamically more favorable than BACE-۱ (-۲۲.۳۵ 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-۱ 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 (PC۱ and PC۲) indicated that the large concerted motions of BACE-۱ found in the simulations were particularly more sensitive to this drug than AChE.

کلیدواژه ها:

Molecular Dynamics Simulation ، Alzheimer's disease ، Motion modes ، Binding free energy ، Free-energy landscape