PDBsum entry 6bfe

Hydrolase/hydrolase inhibitor

PDB id: 6bfe

Contents

Protein chains

393 a.a.

Ligands

DJV ×2

GOL ×5

Waters ×855

PDB id:

6bfe

Name:

Hydrolase/hydrolase inhibitor

Title:

Bace crystal structure with hydroxy pyrrolidine inhibitor

Structure:

Beta-secretase 1. Chain: a, b. Synonym: aspartyl protease 2,asp 2,beta-site amyloid precursor protein cleaving enzyme 1,beta-site app cleaving enzyme 1,memapsin-2, membrane-associated aspartic protease 2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bace1, bace, kiaa1149. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.51Å R-factor: 0.173 R-free: 0.200

Authors:

D.E.Timm

Key ref:

A.B.Bueno et al. (2017). Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences. J Med Chem, 60, 9807-9820. PubMed id: 29088532 DOI: 10.1021/acs.jmedchem.7b01304

Date:

26-Oct-17 Release date: 15-Nov-17

Protein chains

P56817  (BACE1_HUMAN) -  Beta-secretase 1 from Homo sapiens

Seq: 501 a.a.

Struc: 393 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.23.46 - memapsin 2.

DOI no: 10.1021/acs.jmedchem.7b01304

J Med Chem 60:9807-9820 (2017)

PubMed id: 29088532

Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences.

A.B.Bueno, J.Agejas, H.Broughton, R.Dally, T.B.Durham, J.F.Espinosa, R.González, P.J.Hahn, A.Marcos, R.Rodríguez, G.Sanz, J.F.Soriano, D.Timm, P.Vidal, H.C.Yang, J.R.McCarthy.

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.