6EJ3
BACE1 compound 23
Summary for 6EJ3
| Entry DOI | 10.2210/pdb6ej3/pdb |
| Related | 6EJ2 |
| Descriptor | Beta-secretase 1, (1r,4r)-4-methoxy-6'-(5-methyl-3-pyridinyl)-3'H-dispiro[cyclohexane-1,2'-indene-1',4''-[1,3]oxazol]-2''-amine (3 entities in total) |
| Functional Keywords | bace1, protease, alzheimer, peptide binding protein |
| Biological source | Homo sapiens (Human) |
| Cellular location | Membrane; Single-pass type I membrane protein: P56817 |
| Total number of polymer chains | 1 |
| Total formula weight | 56192.97 |
| Authors | Johansson, P. (deposition date: 2017-09-20, release date: 2018-04-18, Last modification date: 2024-11-06) |
| Primary citation | Johansson, P.,Kaspersson, K.,Gurrell, I.K.,Back, E.,Eketjall, S.,Scott, C.W.,Cebers, G.,Thorne, P.,McKenzie, M.J.,Beaton, H.,Davey, P.,Kolmodin, K.,Holenz, J.,Duggan, M.E.,Budd Haeberlein, S.,Burli, R.W. Toward beta-Secretase-1 Inhibitors with Improved Isoform Selectivity. J. Med. Chem., 61:3491-3502, 2018 Cited by PubMed Abstract: BACE1 is responsible for the first step in APP proteolysis, leading to toxic Aβ production, and has been indicated to play a key role in the pathogenesis of Alzheimer's disease. The related isoform BACE2 is thought to be involved in processing of the pigment cell-specific melanocyte protein. To avoid potential effects on pigmentation, we investigated the feasibility for developing isoform-selective BACE1 inhibitors. Cocrystal structures of 47 compounds were analyzed and clustered according to their selectivity profiles. Selective BACE1 inhibitors were found to exhibit two distinct conformational features proximal to the flap and the S3 subpocket. Several new molecules were designed and tested to make use of this observation. The combination of a pyrimidinyl C-ring and a methylcyclohexyl element resulted in lead molecule 28, which exhibited ∼50-fold selectivity. Compared to a nonselective BACE1/2 inhibitor, 28 showed significantly less inhibition of PMEL processing in human melanocytes, indicating good functional selectivity of this inhibitor class. PubMed: 29617572DOI: 10.1021/acs.jmedchem.7b01716 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.94 Å) |
Structure validation
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