@article{bibcite_167,
  keywords = {Models, Molecular, Amyloid Precursor Protein Secretases, Protease Inhibitors, Electrochemistry},
  author = {D. Huang and U. L{\"u}thi and P. Kolb and M. Cecchini and A. Barberis and A. Caflisch},
  title = {In silico discovery of beta-secretase inhibitors},
  abstract = {<p>Alzheimer{\textquoteright}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 <i>in silico</i> 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<sub>50</sub> value lower than 100 \&mu;M 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<sub>50</sub> \&lt; 20 \&mu;M), 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 <i>in silico</i> high-throughput screening approach.</p>},
  year = {2006},
  journal = {Journal of the American Chemical Society},
  volume = {128},
  pages = {5436-5443},
  month = {2006 Apr 26},
  issn = {0002-7863},
  doi = {10.1021/ja0573108},
  language = {eng},
}