title: In silico discovery of beta-secretase inhibitors.
abstract: Alzheimer's disease, the most common amyloid-associated disorder, accounts for the majority of the dementia diagnosed after the age of 60. The cleavage of the beta-amyloid precursor protein is initiated by beta-secretase (BACE-1), a membrane-bound aspartic protease, which has emerged as an important but difficult protein target. Here, an in silico screening approach consisting of fragment-based docking, ligand conformational search by a genetic algorithm, and evaluation of free energy of binding was used to identify low-molecular-weight inhibitors of BACE-1. More than 300,000 small molecules were docked and about 15,000 prioritized according to a linear interaction energy model with evaluation of solvation by continuum electrostatics. Eighty-eight compounds were tested in vitro, and 10 of them showed an IC(50) value lower than 100 microM in a BACE-1 enzymatic assay. Interestingly, the 10 active compounds shared a triazine scaffold. Moreover, four of them were active in an assay with mammalian cells (EC(50) < 20 microM), indicating that they are cell-permeable. Therefore, these triazine derivatives are very promising lead candidates for BACE-1 inhibition. The discoveries of this series and two other series of nonpeptidic BACE-1 inhibitors demonstrate the usefulness of our in silico high-throughput screening approach.
authors.affiliation: Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Danzhi
authors.initials: D
authors.lastname: Huang
authors.forename: Urs
authors.initials: U
authors.lastname: Lüthi
authors.forename: Peter
authors.initials: P
authors.lastname: Kolb
authors.forename: Marco
authors.initials: M
authors.lastname: Cecchini
authors.forename: Alcide
authors.initials: A
authors.lastname: Barberis
authors.forename: Amedeo
authors.initials: A
authors.lastname: Caflisch
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D004563:Electrochemistry; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases