A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC(50) values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyzes were performed on selected compounds, and enzyme-inhibitor interactions are discussed.
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The ability to perform routine structure-guided drug design for selective BACE inhibitors has been limited because of the lack of robust platform for BACE2 expression, purification, and crystallization. To overcome this limitation, we developed a platform that produces 2-3 mg of pure BACE2 protein per liter of culture, and we used this protein to design macrocyclic compounds that potently and selectively inhibit BACE1 over BACE2. Compound was found to potently inhibit BACE 1 ( = 5 nM) with a selectivity of 214-fold over BACE2.
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Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, USA.
We describe a new template-based method for docking flexible ligands such as macrocycles to proteins. It combines Monte-Carlo energy minimization on the manifold, a fast manifold search method, with BRIKARD for complex flexible ligand searching, and with the MELD accelerator of Replica-Exchange Molecular Dynamics simulations for atomistic degrees of freedom. Here we test the method in the Drug Design Data Resource blind Grand Challenge competition.
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J Comput Aided Mol Des
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Department of Pharmaceutical Sciences, University of California, Irvine, CA, 92697, USA.
The Drug Design Data Resource (D3R) Grand Challenges present an opportunity to assess, in the context of a blind predictive challenge, the accuracy and the limits of tools and methodologies designed to help guide pharmaceutical drug discovery projects. Here, we report the results of our participation in the D3R Grand Challenge 4 (GC4), which focused on predicting the binding poses and affinity ranking for compounds targeting the [Formula: see text]-amyloid precursor protein (BACE-1). Our ligand similarity-based protocol using HYBRID (OpenEye Scientific Software) successfully identified poses close to the native binding mode for most of the ligands with less than 2 Å RMSD accuracy.
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Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
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Open Med Chem J
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