Structure and modeling in the design of β‐ and γ‐secretase inhibitors

Abstract

This review discusses the involvement of structure and modeling in the design of b-secretase (BACE-1) and g-secretase inhibitors as putative Alzheimer's Disease therapeutics. The early and broad availability of structural information for BACE-1, a membrane-tethered aspartyl protease, has led to the use of in silico methods in the overall design and optimization process. However, for g-secretase, an integral membrane protein, the lack of a detailed 3D structure has limited the application of computational methods. Drug Dev Res 70 : 70-93, 2009.

The Identification of Biochanin A as a Potent and Selective β-Site App-Cleaving Enzyme 1 (Bace1) Inhibitor

“…β-Secretase and γ-secretase have been identified as the two key proteases responsible for the processing of the membrane-bound APP to the 40/42 residue Aβ [6]. β-APP cleaving enzyme 1 (BACE1) is the main form of β-secretase that cleaves APP to generate Aβ [7].…”

Structure-Based β-Secretase (BACE1) Inhibitors

“…One main goal of the modelling studies is to predict the binding free energy between BACE1 and a ligand. Many approaches have been proposed to handle this problem such as empirical models for scoring functions, theoretical estimations of the free energy of change, models based on linear relationship between binding and computed interaction energy terms incorporating solvation explicitly or implicitly in many force-fields [4,5,45].…”

“…peptides. BACE1 (-secretase 1) was demonstrated to be the rate-limiting enzyme activity in the production of A, suggesting a potentially beneficial effect of -secretase inhibitors in AD [2,[4][5][6][7]. Although aspartic proteases [8] form the smallest protease class with about 15 members in the human genome, this class proved to be one of the richest pool for pharmaceutical research.…”

Effects of solvent fractions of Allomyrina dichotoma larvae through the inhibition of in vitro BACE1 and β‐amyloid(25–35)‐induced toxicity in rat pheochromocytoma PC12 cells

“…This action is limited with processing by sequential α‐secretase (TACE) and γ‐secretase generating soluble and harmless P3 peptides that are not involved in AD development (Holloway et al . ). β‐Site amyloid precursor protein cleaving enzyme 1 (BACE1) is proven to be the vital rate‐limiting enzyme in the formation of Aβ, a critical factor in AD (Cole & Vassar ).…”