Quantitative structure activity relationship analysis of aminoimidazoles as BACE-I inhibitors

Abstract

β-Secretase (BACE-1) is an important and attractive target involved in the pathogenesis of Alzheimer’s disease (AD). The enzyme is involved in the cleavage of amyloid precursor protein (APP) which is the rate-limiting step for the production of Aβ-42. β-Secretase inhibitors inhibit the amyloidogenic cleavage of APP and hence prevent the synthesis of Aβ-42, the cause of AD. A data set of aminoimidazoles was used to study the two-dimensional quantitative structure activity relationships (2D-QSAR) to explore the structural requirements for BACE-1 inhibition. This series of molecules is known to possess BACE-1 inhibitory activity in vivo. 2D-QSAR models were developed using multiple linear regression analysis which were then validated using leave-one-out method. The selected QSAR model displayed significant relationship between descriptors and biological activity along with internal and external predictivity. The developed model was also validated using external data set of hydantoins. The study reveals that thermo-dynamic descriptors (molar refractivity, Log P, van der Waals energy, polar surface area) and steric descriptors (Harary index, Randic index) play important role in β-secretase inhibition. The information generated may be useful for the design of novel and potent β-secretase inhibitors.