3VG1
Crystal Structure of Human Beta Secretase in Complex with NVP-BUR436, derived from a soaking experiment
Summary for 3VG1
| Entry DOI | 10.2210/pdb3vg1/pdb |
| Related | 3VEU 3VF3 4D83 4D85 4D88 4D89 4D8C |
| Descriptor | Beta-secretase 1, (3R,4S,5S)-3-[(3-tert-butylbenzyl)amino]-5-{[3-(2,2-difluoroethyl)-1H-indol-5-yl]methyl}tetrahydro-2H-thiopyran-4-ol 1,1-dioxide (3 entities in total) |
| Functional Keywords | beta-secretase, memapsin2, bace1, aspartic proteinase, alzheimer's disease, enzyme inhibitor complex, structure-based drug design, 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 | 45281.97 |
| Authors | Rondeau, J.M.,Bourgier, E. (deposition date: 2012-01-10, release date: 2012-11-21, Last modification date: 2024-11-06) |
| Primary citation | Rueeger, H.,Lueoend, R.,Rogel, O.,Rondeau, J.M.,Mobitz, H.,Machauer, R.,Jacobson, L.,Staufenbiel, M.,Desrayaud, S.,Neumann, U. Discovery of cyclic sulfone hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides J.Med.Chem., 55:3364-3386, 2012 Cited by PubMed Abstract: Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 μmol/kg demonstrated significant reduction of brain Aβ levels. PubMed: 22380629DOI: 10.1021/jm300069y PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.77 Å) |
Structure validation
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