Factors Influencing the Potency of Alzheimer Inhibitors: Computational and Docking Studies

Density functional theory (B3LYP/6-31G [d]) is performed to study the effect of molecular and electronic structures of the investigated β-secretase 1 (BACE1) Alzheimer’s inhibitors on their biological activities and discuss the correlation between their inhibition efficiencies and quantum chemical descriptors. IC50 values of the investigated compounds are mostly affected by the substituted R2 phenyl moiety. The calculations show that the presence of electron withdrawing group increases the half maximal inhibitory concentration (IC50). Structure–activity relationship studies show that the electronic descriptors, energy of high occupied molecular orbital, ΔE, lipophilicity, hardness, and ionization potential index, are the most significant descriptors for the correlation with IC50. Molecular docking simulation is performed to explain the mode of interaction between the most potent drug and the binding sites of the BACE1 target. A good correlation between the experimental and the theoretical data confirms that the quantum chemical methods are successful tools for the discovery of novel BACE1 drugs