4X2L
Crystal structure of human BACE-1 bound to Compound 6
Summary for 4X2L
| Entry DOI | 10.2210/pdb4x2l/pdb |
| Descriptor | Beta-secretase 1, (4S)-4-(2,4-difluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine, IODIDE ION, ... (7 entities in total) |
| Functional Keywords | beta-secretase, protease, 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 | 47415.60 |
| Authors | Vajdos, F.F.,Parris, K. (deposition date: 2014-11-26, release date: 2015-03-04, Last modification date: 2024-10-23) |
| Primary citation | Butler, C.R.,Brodney, M.A.,Beck, E.M.,Barreiro, G.,Nolan, C.E.,Pan, F.,Vajdos, F.,Parris, K.,Varghese, A.H.,Helal, C.J.,Lira, R.,Doran, S.D.,Riddell, D.R.,Buzon, L.M.,Dutra, J.K.,Martinez-Alsina, L.A.,Ogilvie, K.,Murray, J.C.,Young, J.M.,Atchison, K.,Robshaw, A.,Gonzales, C.,Wang, J.,Zhang, Y.,O'Neill, B.T. Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design. J.Med.Chem., 58:2678-2702, 2015 Cited by PubMed Abstract: The identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid β (Aβ) levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of Aβ-derived plaques. Most importantly, evaluation of 36 in a 2-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors. PubMed: 25695670DOI: 10.1021/jm501833t PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.55 Å) |
Structure validation
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