title: Structure-guided design of β-secretase (BACE-1) inhibitors.
abstract: β-secretase (BACE-1) is a membrane-tethered aspartyl protease that serves as the rate-limiting enzyme in processing the amyloid precursor protein (APP) and, thus, is believed to play a central role in the neurodegenerative disorder, Alzheimer's disease. Due to the availability of X-ray crystal structures for the soluble domain of BACE-1, structure-based methods have been widely employed in the design of BACE-1 inhibitors. A variety of computational methods have been used, ranging from quantum mechanical studies to molecular dynamics calculations and scoring methods, all aimed at understanding the unique chemical features of the BACE-1 active site. However, BACE-1 has proven to be a difficult target due to its extended active site, its intrinsic flexibility and the requirement for brain penetration.
authors.affiliation: Merck Research Laboratories, Molecular Systems, WP53F-301, West Point, PA 19486, USA +1 215 652 7183 ; +1 215 652 4625 ; georgia_mcgaughey@merck.com.
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway