Molecular insight into the interaction mechanism of amino-2H-imidazole derivatives with BACE-1 protease: QM/MM Investigations

VEGA-HISSI, ESTEBAN; TOSSO, RODRIGO DAVID; ENRIZ, RICARDO DANIEL; GUTIERREZ, LUCAS

Congreso; 10th Triennial Congress of the World Association of Theoretical and Computational Chemists; 2014

β-secretase or β-site amyloid precursor protein cleaving enzyme (BACE-1) has been considered as a striking therapeutic target for Alzheimer?s disease (AD) treatment and several attempts have been focused on the development of inhibitors of this key enzyme. Recently, two new amino-2H-imidazole compounds, (R)-1t and (S)-1m, with a very interesting inhibitory profile have been synthesized and co-crystallized within the enzyme active site. In this study, we described quantitatively the interactions between these inhibitors and BACE-1 from a theoretical point of view. We employed a hybrid Quantum Mechanics-Molecular Mechanical (QM/MM) method together with a QTAIM analysis to investigate in details the binding of this class of inhibitors to BACE-1.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 of the inhibitors within the enzyme were stronger when they present 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 presence of a second, lipophilic substituent confered certain additional stability, especially in compound (R)-1t, but became a compromise between permeability and collateral hErg affinity.These results also showed that from relatively simple molecular modeling techniques it was possible to explain the behavior of inhibitors that have a similar affinity for the enzyme. In this sense it is important to point out the accuracy of the combined ONIOM - QTAIM analysis that allows identifying the interactions that account for the activity difference between compounds, even at a nanomolar range.