SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool.
Proc Natl Acad Sci U S A
; 111(29): 10416-21, 2014 Jul 22.
Article
in En
| MEDLINE
| ID: mdl-24972791
ABSTRACT
We demonstrate the use of surface-enhanced Raman spectroscopy (SERS) as an excellent tool for identifying the binding site of small molecules on a therapeutically important protein. As an example, we show the specific binding of the common antihypertension drug felodipine to the oncogenic Aurora A kinase protein via hydrogen bonding interactions with Tyr-212 residue to specifically inhibit its activity. Based on SERS studies, molecular docking, molecular dynamics simulation, biochemical assays, and point mutation-based validation, we demonstrate the surface-binding mode of this molecule in two similar hydrophobic pockets in the Aurora A kinase. These binding pockets comprise the same unique hydrophobic patches that may aid in distinguishing human Aurora A versus human Aurora B kinase in vivo. The application of SERS to identify the specific interactions between small molecules and therapeutically important proteins by differentiating competitive and noncompetitive inhibition demonstrates its ability as a complementary technique. We also present felodipine as a specific inhibitor for oncogenic Aurora A kinase. Felodipine retards the rate of tumor progression in a xenografted nude mice model. This study reveals a potential surface pocket that may be useful for developing small molecules by selectively targeting the Aurora family kinases.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Spectrum Analysis, Raman
/
Protein Kinase Inhibitors
/
Drug Discovery
/
Molecular Dynamics Simulation
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2014
Document type:
Article