PDBsum entry 4d8c

Hydrolase/hydrolase inhibitor

PDB id: 4d8c

Contents

Protein chains

377 a.a.

Ligands

BXD ×3

SO4 ×2

Waters ×704

PDB id:

4d8c

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of human beta secretase in complex with nvp-bxd552, derived from a co-crystallization experiment

Structure:

Beta-secretase 1. Chain: a, b, c. Fragment: catalytic domain (unp residues 48-447). Synonym: aspartyl protease 2, asp2, 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: bace, bace1, kiaa1149. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.07Å R-factor: 0.193 R-free: 0.211

Authors:

J.M.Rondeau,E.Bourgier

Key ref:

H.Rueeger et al. (2012). Discovery of cyclic sulfone hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure-based design and in vivo reduction of amyloid β-peptides. J Med Chem, 55, 3364-3386. PubMed id: 22380629

Date:

10-Jan-12 Release date: 21-Nov-12

Protein chains

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

Seq: 501 a.a.

Struc: 377 a.a.

Enzyme reactions

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

J Med Chem 55:3364-3386 (2012)

PubMed id: 22380629

Discovery of cyclic sulfone hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure-based design and in vivo reduction of amyloid β-peptides.

H.Rueeger, R.Lueoend, O.Rogel, J.M.Rondeau, H.Möbitz, R.Machauer, L.Jacobson, M.Staufenbiel, S.Desrayaud, U.Neumann.

ABSTRACT

Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 μmol/kg demonstrated significant reduction of brain Aβ levels.