dc.contributor.author |
Karthigeyan, Dhanasekaran
|
|
dc.contributor.author |
Siddhanta, Soumik
|
|
dc.contributor.author |
Kishore, Annavarapu Hari
|
|
dc.contributor.author |
Perumal, Sathya S. R. R.
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|
dc.contributor.author |
Agren, Hans
|
|
dc.contributor.author |
Sudevan, Surabhi
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|
dc.contributor.author |
Bhat, Akshay V.
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|
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 |