title: Ensemble-docking approach on BACE-1: pharmacophore perception and guidelines for drug design.
abstract: Beta-secretase (BACE-1), a key enzyme in the etiopathogenesis and progression of Alzheimer disease, is the focus of medicinal chemistry efforts both in the pharmaceutical industry and in academia. Despite the availability of diverse peptidomimetic BACE-1 inhibitors, nonpeptidic compounds suitable for oral delivery and transport across the blood brain barrier are in great demand. Herein, a number of active and structurally diverse inhibitors were selected and subjected to an ensemble-docking process into five BACE-1 X-ray structures. The calculated bioactive conformations of these inhibitors allowed us to build an exhaustive pharmacophore model, which captures both the common geometric and electronic features essential for enzyme inhibition. The model is intended to aid the rational design of new BACE-1 inhibitors. Furthermore, a comparison of BACE/cathepsin D X-ray structures was made to provide guidelines for the design of BACE-selective inhibitors.
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Hannes A
authors.initials: HA
authors.lastname: Braun
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D020134:Catalytic Domain; D015195:Drug Design; D013237:Stereoisomerism
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human