INVESTIGADORES
ENRIZ Ricardo Daniel
artículos
Título:
Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM Study
Autor/es:
E G VEGA-HISSI,[; R TOSSO; R D ENRIZ; L J GUTIERREZ
Revista:
INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY
Editorial:
JOHN WILEY & SONS INC
Referencias:
Lugar: New York; Año: 2015 vol. 115 p. 389 - 397
ISSN:
0020-7608
Resumen:
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 mechanicsmolecular
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.