In silico discovery of beta-secretase inhibitors Export

@article{2937, 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.}, author = {Huang, Danzhi and Lüthi, Urs and Kolb, Peter and Cecchini, Marco and Barberis, Alcide and Caflisch, Amedeo}, citeulike-article-id = {5686645}, citeulike-linkout-0 = {http://www.ncbi.nlm.nih.gov/pubmed/16620115}, comment = {In silico discovery of beta-secretase inhibitors}, journal = {Journal of the American Chemical Society}, keywords = {file-import-09-08-31}, number = {16}, pages = {5436-43+}, posted-at = {2009-08-31 01:15:25}, priority = {2}, title = {In silico discovery of beta-secretase inhibitors}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16620115}, volume = {128}, year = {2006} }

TY - JOUR ID - 2937 L3 - citeulike-article-id:5686645 N2 - 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. IS - 16 JF - Journal of the American Chemical Society TI - In silico discovery of beta-secretase inhibitors VL - 128 SP - 5436-43 KW - file-import-09-08-31 N1 - In silico discovery of beta-secretase inhibitors AU - Huang, Danzhi AU - Lüthi, Urs AU - Kolb, Peter AU - Cecchini, Marco AU - Barberis, Alcide AU - Caflisch, Amedeo PY - 2006/// UR - http://www.ncbi.nlm.nih.gov/pubmed/16620115 ER -