SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool

Karthigeyan, Dhanasekaran and Siddhanta, Soumik and Kishore, Annavarapu Hari and Perumal, Sathya S. R. R. and Agrend, Hans and Surabhi Sudevan, and Bhat, Akshay V. and Balasubramanyam, K. and Rangappa, K. S. and Kundu, Tapas K. and Narayana, Chandrabhas (2014) 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 , 111 (29). pp. 10416-10421.

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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.

Item Type: Article
Additional Information: Unmapped bibliographic data: JO - Proceedings of the National Academy of Sciences [Field not mapped to EPrints]
Subjects: Physical Sciences > Chemistry
Divisions: PG Campuses > Manasagangotri, Mysore > Chemistry
Depositing User: Praveen Kumari B.L
Date Deposited: 10 Jul 2014 11:27
Last Modified: 30 Oct 2015 11:44

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