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

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dc.contributor.author Karthigeyan, Dhanasekaran
dc.contributor.author Siddhanta, Soumik
dc.contributor.author Kishore, Annavarapu Hari
dc.contributor.author Perumal, Sathya S. R. R.
dc.contributor.author Agren, Hans
dc.contributor.author Sudevan, Surabhi
dc.contributor.author Bhat, Akshay V.
dc.contributor.author Balasubramanyam, Karanam
dc.contributor.author Subbegowda, Rangappa Kanchugarakoppal
dc.contributor.author Kundu, Tapas Kumar
dc.contributor.author Narayana, Chandrabhas
dc.date.accessioned 2017-02-16T11:32:48Z
dc.date.available 2017-02-16T11:32:48Z
dc.date.issued 2014
dc.identifier.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 en_US
dc.identifier.citation Proceedings of The National Academy of Sciences of The United States of America en_US
dc.identifier.citation 111 en_US
dc.identifier.citation 29 en_US
dc.identifier.issn 0027-8424
dc.identifier.uri https://libjncir.jncasr.ac.in/xmlui/10572/2313
dc.description Restricted Access en_US
dc.description.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. en_US
dc.description.uri http://dx.doi.org/10.1073/pnas.1402695111 en_US
dc.language English en
dc.language.iso English en_US
dc.publisher National Academy of Sciences en_US
dc.rights @National Academy of Sciences, 2014 en_US
dc.subject Vibrational Spectroscopy en_US
dc.subject Structure-Activity Relationship en_US
dc.subject Ligand Binding en_US
dc.subject Surface-Enhanced Raman en_US
dc.subject Small-Molecule Inhibitor en_US
dc.subject Protein-Ligand Interactions en_US
dc.subject Aurora-A Kinase en_US
dc.subject Histone Acetyltransferase en_US
dc.subject Multidrug-Resistance en_US
dc.subject Crystal-ructure en_US
dc.subject In-Vivo en_US
dc.subject Felodipine en_US
dc.subject Mln8054 en_US
dc.title SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool en_US
dc.type Article en_US


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