Molecular insight into the interaction mechanisms of amino-2H -imidazole derivatives with BACE1 protease: A QM/MM and QTAIM study

Abstract

In this study, we described quantitatively the interactions between two new amino‐2H‐imidazole inhibitors ((R)‐1t and (S)‐1m) and BACE1 using a hybrid quantum mechanics‐molecular mechanical (QM/MM) method together with a quantum theory of atoms In Molecules (QTAIM) analysis. Our computational calculations revealed that the binding affinity of these compounds is mostly related to the amino‐2H‐imidazole core, which interact tightly with the aspartate dyad of the active site. The interactions were stronger when the inhibitors presented a bulky substituent with a hydrogen bond acceptor motif pointing toward Trp76, such as the 3,5‐dimethyl‐4‐methoxyphenyl group of compound (S)‐1m. Furthermore, the QTAIM analysis revealed that many hydrophobic interactions complement cooperatively the hydrogen bond which is not present when compound (R)‐1t is bound to the enzyme. The combined QM/MM‐QTAIM analysis allows identifying the interactions that account for the activity difference between compounds, even at a nanomolar range.

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“…Various molecules have been studied and evaluated for their inhibitory action against BACE1 including macrocyclic lactones, hydroethylenes, aminoethylenes, aminoimidazoles, aminobenzthiazines, spiropiperidines, etc. [108,109,110,111,112,113,114].…”

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“…After the QM/MM calculation, the optimized geometries were used as input for QTAIM analysis (Bader, 1985), which was performed with the help of Multiwfn software (Lu and Chen, 2012) using the wave functions generated at the B3LYP-D/6-31G (d) level. This type of calculation has been used in recent studies because it ensures a reasonable compromise between the wave function quality required to obtain reliable values of ρ(r) and the available computer power, considering the extension of the system in the study (Andujar et al, 2012;Gutierrez et al, 2016;Tosso et al, 2013;Vega-Hissi et al, 2015).…”

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