3U6A

Rational Design and Synthesis of Aminopiperazinones as Beta Secretase (BACE) Inhibitors

PDB DOI: https://doi.org/10.2210/pdb3U6A/pdb

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

Deposited: 2011-10-12 Released: 2011-11-09
Deposition Author(s): Spurlino, J.C., Alexander, R.S.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.20 Å
R-Value Free: 0.237
R-Value Work: 0.187
R-Value Observed: 0.189

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Rational design and synthesis of aminopiperazinones as beta-secretase (BACE) inhibitors.

Tresadern, G., Delgado, F., Delgado, O., Gijsen, H., Macdonald, G.J., Moechars, D., Rombouts, F., Alexander, R., Spurlino, J., Van Gool, M., Vega, J.A., Trabanco, A.A.

(2011) Bioorg Med Chem Lett 21: 7255-7260

PubMed: 22071305 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2011.10.050
Primary Citation of Related Structures:
3U6A

PubMed Abstract:
Aminopiperazinone inhibitors of BACE were identified by rational design. Structure based design guided idea prioritization and initial racemic hit 18a showed good activity. Modification in decoration and chiral separation resulted in the 40 nM inhibitor, (-)-37, which showed in vivo reduction of amyloid beta peptides. The crystal structure of 18a showed a binding mode driven by interaction with the catalytic aspartate dyad and distribution of the biaryl amide decoration towards S1 and S3 pockets.

Organizational Affiliation

Research Informatics & Integrative Genomics, Calle Jarama 75, Poligono Industrial, Toledo 45007, Spain. gtresade@its.jnj.com

Macromolecule Content

Total Structure Weight: 132.13 kDa
Atom Count: 9,761
Modelled Residue Count: 1,144
Deposited Residue Count: 1,170
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Beta-secretase 1	A, B, C	390	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 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
18P Query on 18P Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain H [auth B] SDF format, chain M [auth C] MOL2 format, chain D [auth A] MOL2 format, chain H [auth B] MOL2 format, chain M [auth C]	D [auth A], H [auth B], M [auth C]	N-{3-[(2R)-6-amino-2,4-dimethyl-3-oxo-2,3,4,5-tetrahydropyrazin-2-yl]phenyl}-5-chloropyridine-2-carboxamide C₁₈ H₁₈ Cl N₅ O₂ MRYFMHAPTQCQLE-GOSISDBHSA-N		Interactions Focus chain D [auth A] Focus chain H [auth B] Focus chain M [auth C] Interactions & Density Focus chain D [auth A] Focus chain H [auth B] Focus chain M [auth C]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain I [auth B] SDF format, chain J [auth B] SDF format, chain L [auth B] SDF format, chain N [auth C] SDF format, chain K [auth B] SDF format, chain O [auth C] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] MOL2 format, chain L [auth B] MOL2 format, chain N [auth C] MOL2 format, chain K [auth B] MOL2 format, chain O [auth C]	E [auth A] F [auth A] G [auth A] I [auth B] J [auth B] E [auth A], F [auth A], G [auth A], I [auth B], J [auth B], K [auth B], L [auth B], N [auth C], O [auth C]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B] Focus chain N [auth C] Focus chain O [auth C] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B] Focus chain N [auth C] Focus chain O [auth C]