6BFW

BACE crystal structure with hydroxy morpholine inhibitor

Summary for 6BFW

• Entry DOI: 10.2210/pdb6bfw/pdb
• Descriptor: Beta-secretase 1, N-[(1S,2S)-1-[(3R,6R)-6-(cyclohexylmethoxy)morpholin-3-yl]-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl]acetamide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: bace1, beta-secretase, inhibitor, protease, hydrolase, 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: 2
• Total formula weight: 99069.51

Authors

Timm, D.E. (deposition date: 2017-10-27, release date: 2017-11-15, Last modification date: 2024-11-06)

Primary citation

Bueno, A.B.,Agejas, J.,Broughton, H.,Dally, R.,Durham, T.B.,Espinosa, J.F.,Gonzalez, R.,Hahn, P.J.,Marcos, A.,Rodriguez, R.,Sanz, G.,Soriano, J.F.,Timm, D.,Vidal, P.,Yang, H.C.,McCarthy, J.R.
Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences.
J. Med. Chem., 60:9807-9820, 2017

PubMed Abstract: NMR conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines, or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1', and S2' pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogues, have been found to be brain penetrant BACE-1 inhibitors.

PubMed: 29088532
DOI: 10.1021/acs.jmedchem.7b01304

Experimental method

X-RAY DIFFRACTION (1.84 Å)