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

Karthigeyan, Dhanasekaran ; Siddhanta, Soumik ; Kishore, Annavarapu Hari ; Perumal, Sathya S. R. R. ; Agren, Hans ; Sudevan, Surabhi ; Bhat, Akshay V. ; Balasubramanyam, Karanam ; Subbegowda, Rangappa Kanchugarakoppal ; Kundu, Tapas K. ; 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. ISSN 0369-3236

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Official URL: http://www.pnas.org/content/111/29/10416.full

Related URL: http://dx.doi.org/10.1073/pnas.1402695111

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.

Item Type:Article
Source:Copyright of this article belongs to Indian National Science Academy.
Keywords:Vibrational Spectroscopy; Structure–activity Relationship; Ligand Binding
ID Code:113611
Deposited On:23 Apr 2018 12:14
Last Modified:23 Apr 2018 12:14

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