4EXG

Design and synthesis of potent hydroxyethylamine (hea) bace-1 inhibitors

PDB DOI: https://doi.org/10.2210/pdb4EXG/pdb

Classification: HYDROLASE/HYDROLASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2012-04-30 Released: 2012-10-31
Deposition Author(s): Borkakoti, N., Lindberg, J., Derbyshire, D.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.80 Å
R-Value Free: 0.227
R-Value Work: 0.178
R-Value Observed: 0.181

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.0 of the entry. See complete history.

Literature

Design and synthesis of potent hydroxyethylamine (HEA) BACE-1 inhibitors carrying prime side 4,5,6,7-tetrahydrobenzazole and 4,5,6,7-tetrahydropyridinoazole templates.

Sund, C., Belda, O., Borkakoti, N., Lindberg, J., Derbyshire, D., Vrang, L., Hamelink, E., Hgren, C., Woestenenk, E., Wikstrom, K., Eneroth, A., Lindstrom, E., Kalayanov, G.

(2012) Bioorg Med Chem Lett 22: 6721-6727

PubMed: 23010268 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2012.08.097
Primary Citation of Related Structures:
4EWO, 4EXG

PubMed Abstract:
A set of low molecular weight compounds containing a hydroxyethylamine (HEA) core structure with different prime side alkyl substituted 4,5,6,7-tetrahydrobenzazoles and one 4,5,6,7-tetrahydropyridinoazole was synthesized. Striking differences were observed on potencies in the BACE-1 enzymatic and cellular assays depending on the nature of the heteroatoms in the bicyclic ring, from the low active compound 4 to inhibitor 6, displaying BACE-1 IC(50) values of 44 nM (enzyme assay) and 65 nM (cell-based assay).

Organizational Affiliation

Medivir AB, Lunastigen 7, SE-14144 Huddinge, Sweden.

Macromolecule Content

Total Structure Weight: 43.48 kDa
Atom Count: 3,504
Modelled Residue Count: 377
Deposited Residue Count: 386
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Beta-secretase 1	A	386	Homo sapiens	Mutation(s): 0 Gene Names: BACE1, BACE, KIAA1149 EC: 3.4.23.46
UniProt & NIH Common Fund Data Resources
Find proteins for P56817 (Homo sapiens) Explore P56817 Go to UniProtKB: P56817
PHAROS: P56817 GTEx: ENSG00000186318
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P56817
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
916 Query on 916 Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A]	B [auth A]	N-[(2S,3R)-4-{[(4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H-thieno[2,3-b]pyran-4-yl]amino}-3-hydroxy-1-phenylbutan-2-yl]acetamide C₂₆ H₃₈ N₂ O₃ S YLIBYDKWVPKMKX-RJGXRXQPSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
916	PDBBind: 4EXG	IC50: 8.5 (nM) from 1 assay(s)
916	Binding MOAD: 4EXG	IC50: 8.5 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.80 Å
R-Value Free: 0.227
R-Value Work: 0.178
R-Value Observed: 0.181
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 48.223	α = 90
b = 76.371	β = 90
c = 104.377	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
PDB_EXTRACT	data extraction
DNA	data collection
MOSFLM	data reduction
SCALEPACK	data scaling
PHASER	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2012-10-31

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2012-10-31
Type: Initial release

RCSB PDB Core Operations are funded by the National Science Foundation (DBI-1832184), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM133198.