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

ESTEBAN VEGA-HISSI; TOSSO RODRIGO; ENRIZ, RICARDO D.; GUTIÉRREZ LUCAS JOEL

Congreso; 10th Congress of theWorld Association of Theoretical and Computational Chemists (WATOC); 2014

  Molecular insight into the interaction mechanism of  amino-2H-imidazole derivatives with BACE-1 protease: QM/MM Investigations   Esteban G. Vega-Hissia, Rodrigo Tossob, Ricardo D. Enrizb , Lucas J. Gutierrezc aFQByF, and IMIBIO-CONICET, Universidad Nacional de San Luis, Chacabuco 917, (5700) San Luis, Argentina; e-mail: egvega@unsl.edu.ar; bAddress Author 2; e-mail: name@server.domain (Cambria 12 points, italic)     Abstract   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 [1].  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.     Acknowledgments: Author 1 acknowledges FONDECYT for financial support, Author 2 acknowledges Professor P. McCartney for helpful discussions.   References:   [1] Ylva Gravenfors et al. J. Med. Chem. 55 (2012) 9297.