Structure-based design and synthesis of novel P2/P3 modified, non-peptidic beta-secretase (BACE-1) inhibitors
ABSTRACT Starting from peptidomimetic BACE-1 inhibitors, the P2 amino acid including the P2/P3 peptide bond was replaced by a rigid 3-aminomethyl cyclohexane carboxylic acid. Co-crystallization revealed an unexpected binding mode with the P3/P4 amide bond placed into the S3 pocket resulting in a new hydrogen bond interaction pattern. Further optimization based on this structure resulted in highly potent BACE-1 inhibitors with selectivity over BACE-2 and cathepsin D.
SourceAvailable from: Ulf NeumannBioorganic & Medicinal Chemistry Letters 04/2013; 23(8):2460–2461. DOI:10.1016/j.bmcl.2013.01.001 · 2.33 Impact Factor
Journal of Alzheimer's disease: JAD 01/2013; 33(3):547-658. · 3.61 Impact Factor
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ABSTRACT: 3D shape- or volume-based virtual screening is a broadly used approach in drug discovery. In recent years a large number of publications have appeared in which these tools were compared to not only competitive methods but to docking studies as well. Studies often showed that the effectiveness of docking could be highly variable due to a large number of possible confounding factors, while ligand-based, shape-based approaches were more consistent. Here, we describe a novel, fully flexible shape-based virtual screening algorithm that does not require previous 3D conformation or conformer generation. Due to its solid consistency it can easily be used on desktop computers by non-expert scientists. The algorithm is demonstrated in a study for the investigation of ß-secretase inhibitors.Journal of Chemical Information and Modeling 02/2014; 54(4). DOI:10.1021/ci400620f · 4.07 Impact Factor