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

Dhanasekaran Karthigeyan; Soumik Siddhanta; Annavarapu Hari KishoreSathya S. R. R. PerumalHans ?grenSurabhi SudevanAkshay V. BhatKaranam BalasubramanyamRangappa Kanchugarakoppal SubbegowdaTapas K. KunduChandrabhas Narayana

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

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

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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.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第29期|10416-10421|共6页
作者
Dhanasekaran Karthigeyan; Soumik Siddhanta; Annavarapu Hari KishoreSathya S. R. R. PerumalHans ?grenSurabhi SudevanAkshay V. BhatKaranam BalasubramanyamRangappa Kanchugarakoppal SubbegowdaTapas K. KunduChandrabhas Narayana;
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作者单位

Light Scattering Laboratory, Chemistry and Physics of Materials Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India;

Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India;

Department of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, Roslagstullsbacken 15, SE-114 21 Stockholm, SwedenTranscription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
vibrational spectroscopy; structure–activity relationship; ligand binding;

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

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