3MSK

Fragment Based Discovery and Optimisation of BACE-1 Inhibitors

PDB DOI: https://doi.org/10.2210/pdb3MSK/pdb

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

Deposited: 2010-04-29 Released: 2010-07-14
Deposition Author(s): Smith, M.A., Madden, J.M., Barker, J., Godemann, R., Kraemer, J., Hallett, D.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.264
R-Value Work: 0.223
R-Value Observed: 0.225

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.4 of the entry. See complete history.

Literature

Fragment-based discovery and optimization of BACE1 inhibitors.

Madden, J., Dod, J.R., Godemann, R., Kraemer, J., Smith, M., Biniszkiewicz, M., Hallett, D.J., Barker, J., Dyekjaer, J.D., Hesterkamp, T.

(2010) Bioorg Med Chem Lett 20: 5329-5333

PubMed: 20656487 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2010.06.089
Primary Citation of Related Structures:
3MSJ, 3MSK, 3MSL, 3S2O

PubMed Abstract:
A novel series of 2-aminobenzimidazole inhibitors of BACE1 has been discovered using fragment-based drug discovery (FBDD) techniques. The rapid optimization of these inhibitors using structure-guided medicinal chemistry is discussed.

Organizational Affiliation

Evotec UK Ltd, Abingdon, UK. [email protected]

Macromolecule Content

Total Structure Weight: 46 kDa
Atom Count: 3,275
Modelled Residue Count: 378
Deposited Residue Count: 408
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	408	Homo sapiens	Mutation(s): 0 Gene Names: BACE, BACE1, 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 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
EV4 Query on EV4 Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	4-(2-amino-5-chloro-1H-benzimidazol-1-yl)-N-cyclohexyl-N-methylbutanamide C₁₈ H₂₅ Cl N₄ O UIWHCBCBZBYNDS-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
IOD Query on IOD Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	IODIDE ION I XMBWDFGMSWQBCA-UHFFFAOYSA-M		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
EV4	BindingDB: 3MSK	IC50: 2.60e+4 (nM) from 1 assay(s)
EV4	PDBBind: 3MSK	IC50: 2.60e+4 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.264
R-Value Work: 0.223
R-Value Observed: 0.225
Space Group: P 6₁ 2 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 102.51	α = 90
b = 102.51	β = 90
c = 170.528	γ = 120

Software Package:

Software Name	Purpose
DNA	data collection
PHASER	phasing
REFMAC	refinement
MOSFLM	data reduction
SCALA	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2010-07-14

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2010-07-14
Type: Initial release
Version 1.1: 2011-07-13
Changes: Version format compliance
Version 1.2: 2018-01-24
Changes: Advisory, Structure summary
Version 1.3: 2023-09-06
Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description
Version 1.4: 2024-11-06
Changes: Structure summary