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

Karthigeyan, D. and Siddhanta, S. and Kishore, A. H. and Perumal, Sathya S. R. R. and Agren, H. and Sudevan, S. and Bhat, Akshay V. and Balasubramanyam, K. and Rangappa, K. S. and Kundu, Tapas K. and Narayana, C. (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 of the United States of America, 111 (29). pp. 10416-10421. ISSN 0027-8424

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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
Uncontrolled Keywords:	controlled study, human, human cell, in vivo study, Animals, Humans, Dose-Response Relationship, Drug, female, ligand binding, molecular docking, tumor growth, molecular dynamics, priority journal, enzyme activity, cell proliferation, hydrogen bond, surface property, article, Drug Discovery, Reproducibility of Results, hydrophobicity, Cell Death, protein protein interaction, Neoplasms, Raman spectrometry, Mice, Molecular Dynamics Simulation, Disease Progression, protein structure, hypertension, amlodipine, felodipine, nicardipine, Raman, Spectrum Analysis, Kinetics, Surface Properties, Nude, smooth muscle fiber, aneuploidy, aurora B kinase, Aurora Kinase A, Aurora Kinase B, Binding, cancer risk, Cell Cycle, Competitive, conformational transition, Felodipine, heart rate, HeLa Cells, histone phosphorylation, nimodipine, nitrendipine, point mutation, Protein Kinase Inhibitors, Spindle Poles, structure-activity relationship, surface enhanced Raman spectroscopy, vibrational spectroscopy
Subjects:	C Chemical Science > Chemistry
Divisions:	Department of > Chemistry
Depositing User:	Arshiya Kousar Library Assistant
Date Deposited:	26 Jun 2019 06:58
Last Modified:	12 Jul 2022 07:02
URI:	http://eprints.uni-mysore.ac.in/id/eprint/3680

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