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|Title:||SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool|
Kishore, Annavarapu Hari
Perumal, Sathya S. R. R.
Bhat, Akshay V.
Subbegowda, Rangappa Kanchugarakoppal
Kundu, Tapas Kumar
|Publisher:||National Academy of Sciences|
|Citation:||Karthigeyan, D; Siddhanta, S; Kishore, AH; Perumal, SSRR; Agren, H; Sudevan, S; Bhat, AV; Balasubramanyam, K; Subbegowda, RK; Kundu, TK; Narayana, C, SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool. Proceedings of The National Academy of Sciences of The United States of America 2014, 111 (29) 10416-10421, http://dx.doi.org/10.1073/pnas.1402695111|
Proceedings of The National Academy of Sciences of The United States of America
|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.|
|Appears in Collections:||Research Articles (Chandrabhas N.)|
Research Papers (Tapas K. Kundu)
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