4DPF
BACE-1 in complex with a HEA-macrocyclic type inhibitor
Summary for 4DPF
| Entry DOI | 10.2210/pdb4dpf/pdb |
| Related | 4DPI |
| Descriptor | Beta-secretase 1, N-[(4S,8E,11S)-4-[(1R)-1-hydroxy-2-{[3-(propan-2-yl)benzyl]amino}ethyl]-2,13-dioxo-11-phenyl-6-oxa-3,12-diazabicyclo[12.3.1]octadeca-1(18),8,14,16-tetraen-16-yl]-N-methylmethanesulfonamide (3 entities in total) |
| Functional Keywords | bace1, asp2, bace, macrocycle, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Membrane; Single-pass type I membrane protein: P56817 |
| Total number of polymer chains | 1 |
| Total formula weight | 44250.01 |
| Authors | Lindberg, J.,Borkakoti, N.,Derbyshire, D. (deposition date: 2012-02-13, release date: 2012-07-11, Last modification date: 2024-10-16) |
| Primary citation | Sandgren, V.,Agback, T.,Johansson, P.O.,Lindberg, J.,Kvarnstrom, I.,Samuelsson, B.,Belda, O.,Dahlgren, A. Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: design, synthesis and X-ray crystal structures of enzyme inhibitor complexes. Bioorg.Med.Chem., 20:4377-4389, 2012 Cited by PubMed Abstract: 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. PubMed: 22698785DOI: 10.1016/j.bmc.2012.05.039 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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