3WB5: Crystal Structure of beta secetase in complex with (6S)-2-amino-3,6-dimethyl-6-[(1R,2R)-2-phenylcyclopropyl]-3,4,5,6-tetrahydropyrimidin-4-one

Citation:
Abstract
For further investigation of BACE1 inhibitors using conformational restriction with sp(3) hybridized carbon, we applied this approach to 6-substituted aminopyrimidone derivatives 3 to improve the inhibitory activity by reducing the entropic energy loss upon binding to BACE1. Among eight stereoisomers synthesized, [trans-(1'R,2'R),6S] isomer 6 exhibited the best BACE1 inhibitory activity, which was statistically superior to that of the corresponding ethylene linker compound (R)-3. Combinational examinations of the binding mode of 6 were performed, which included isothermal titration calorimetry (ITC), X-ray crystallographic structure analysis and theoretical calculations, to clarify the effect of our conformational restriction approach. From the ITC measurement, the binding entropy of 6 was found to be approximately 0.5kcal larger than that of (R)-3, which is considered to be affected by conformational restriction with a cyclopropane ring.
PDB ID: 3WB5Download
MMDB ID: 114210
PDB Deposition Date: 2013/5/13
Updated in MMDB: 2017/12
Experimental Method:
x-ray diffraction
Resolution: 2.501  Å
Source Organism:
Similar Structures:
Biological Unit for 3WB5: monomeric; determined by author and by software (PISA)
Molecular Components in 3WB5
Label Count Molecule
Protein (1 molecule)
1
Beta-secretase 1(Gene symbol: BACE1)
Molecule annotation
Chemicals (7 molecules)
1
3
2
2
3
1
4
1
* Click molecule labels to explore molecular sequence information.

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