Ab initio modeling of a potent isophthalamide-based BACE-1 inhibitor: amino acid decomposition analysis

Abstract

β-Secretase or β-site amyloid precursor protein cleaving enzyme (BACE-1) is a membrane-associated aspartyl protease that catalyzes the first step in the formation of amyloid β plaques responsible for Alzheimer’s disease (AD). β-Secretase has been considered as a striking therapeutic target for AD. Recently, several attempts have been focused on the development of inhibitors of this key protease. Among small molecules, scaffolds based on isophthalamide derivatives have been reported as potent non-peptidic BACE-1 inhibitors. In the present study, interactions of a 5-(N-methylmethan-4-ylsulfonamido) isophthalamide-based scaffold with BACE-1 active site residues have been evaluated via the functional B3LYP in association with split valence basis set using polarization functions (Def2-SVP). The complex ligand–receptor system including N1-(4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-(N-methylmethan-4-ylsulfonamido)-N3(1-phenylethyl) isophthalamide (5HA) and 18 amino acids constructing BACE-1 active site exhibited H-bonds, π–π stacking, and Van der Waals interactions associated with total binding energy of −268.34 kcal/mol at B3LYP/Def2-SVP level. The outcomes of conformational analysis postulated that the studied isophthalamide-based structure might not necessarily interact with the active site of BACE-1 in its optimum geometric conformation. Amino acid decomposition analysis on complex ligand–receptor system comprising N1-(4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-(N-methylmethan-4-ylsulfonamido)-N3(1 phenylethyl) isophthalamide and BACE-1 active site was performed using B3LYP method in association with split valence basis set using polarization functions (Def2-SVP).