3UDJ
Crystal Structure of BACE with Compound 5
Summary for 3UDJ
| Entry DOI | 10.2210/pdb3udj/pdb |
| Related | 3UDH 3UDK 3UDM 3UDN 3UDP 3UDQ 3UDR 3UDY |
| Descriptor | Beta-secretase 1, methyl (3S,5'R)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate, 1,2-ETHANEDIOL, ... (6 entities in total) |
| Functional Keywords | 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 | 45698.66 |
| Authors | Efremov, I.V.,Vajdos, F.F.,Borzilleri, K.,Capetta, S.,Dorff, P.,Dutra, J.,Mansour, M.,Oborski, C.,O'Connell, T.,O'Sullivan, T.J.,Pandit, J.,Wang, H.,Withka, J. (deposition date: 2011-10-28, release date: 2012-04-18, Last modification date: 2024-10-30) |
| Primary citation | Efremov, I.V.,Vajdos, F.F.,Borzilleri, K.A.,Capetta, S.,Chen, H.,Dorff, P.H.,Dutra, J.K.,Goldstein, S.W.,Mansour, M.,McColl, A.,Noell, S.,Oborski, C.E.,O'Connell, T.N.,O'Sullivan, T.J.,Pandit, J.,Wang, H.,Wei, B.,Withka, J.M. Discovery and optimization of a novel spiropyrrolidine inhibitor of {beta}-secretase (BACE1) through fragment-based drug design. J.Med.Chem., 55:9069-9088, 2012 Cited by PubMed Abstract: The aspartyl protease β-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of Aβ-peptide, a major component of plaques in the brains of Alzheimer's disease (AD) patients, and inhibition of this enzyme has emerged as a major strategy for pharmacologic intervention in AD. An X-ray-based fragment screen of Pfizer's proprietary fragment collection has resulted in the identification of a novel BACE binder featuring spiropyrrolidine framework. Although exhibiting only weak inhibitory activity against the BACE enzyme, the small compound was verified by biophysical and NMR-based methods as a bona fide BACE inhibitor. Subsequent optimization of the lead compound, relying heavily on structure-based drug design and computational prediction of physiochemical properties, resulted in a nearly 1000-fold improvement in potency while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability. PubMed: 22468999DOI: 10.1021/jm201715d PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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