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Molecular insight into the interaction mechanisms of amino‐2 H ‐imidazole derivatives with BACE1 protease: A QM/MM and QTAIM study
Author(s) -
VegaHissi Esteban Gabriel,
Tosso Rodrigo,
Enriz Ricardo Daniel,
Gutierrez Lucas Joel
Publication year - 2015
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.24854
Subject(s) - chemistry , imidazole , substituent , hydrogen bond , atoms in molecules , stereochemistry , molecule , computational chemistry , organic chemistry
In this study, we described quantitatively the interactions between two new amino‐2 H ‐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‐2 H ‐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.