SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool
2014 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 29, 10416-10421 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2014. Vol. 111, no 29, 10416-10421 p.
vibrational spectroscopy, structure-activity relationship, ligand binding
IdentifiersURN: urn:nbn:se:kth:diva-149506DOI: 10.1073/pnas.1402695111ISI: 000339310700021ScopusID: 2-s2.0-84904659991OAI: oai:DiVA.org:kth-149506DiVA: diva2:739976
QC 201408222014-08-222014-08-222015-06-23Bibliographically approved