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.