Please use this identifier to cite or link to this item: http://lib.jncasr.ac.in:8080/jspui/handle/10572/2313
Title: SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool
Authors: 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 Kumar
Narayana, Chandrabhas
Keywords: Vibrational Spectroscopy
Structure-Activity Relationship
Ligand Binding
Surface-Enhanced Raman
Small-Molecule Inhibitor
Protein-Ligand Interactions
Aurora-A Kinase
Histone Acetyltransferase
Multidrug-Resistance
Crystal-ructure
In-Vivo
Felodipine
Mln8054
Issue Date: 2014
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
111
29
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.
Description: Restricted Access
URI: http://hdl.handle.net/10572/2313
ISSN: 0027-8424
Appears in Collections:Research Articles (Chandrabhas N.)
Research Papers (Tapas K. Kundu)

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