title: SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool.
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.
authors: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit.
authors: Dhanasekaran
authors: D
authors: Karthigeyan
authors: Light Scattering Laboratory, Chemistry and Physics of Materials Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India;
authors: Soumik
authors: S
authors: Siddhanta
authors: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India; and.
authors: Annavarapu Hari
authors: AH
authors: Kishore
authors: Department of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, Roslagstullsbacken 15, SE-114 21 Stockholm, Sweden.
authors: Sathya S R R
authors: SS
authors: Perumal
authors: Department of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, Roslagstullsbacken 15, SE-114 21 Stockholm, Sweden.
authors: Hans
authors: H
authors: Ågren
authors: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit.
authors: Surabhi
authors: S
authors: Sudevan
authors: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit.
authors: Akshay V
authors: AV
authors: Bhat
authors: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit.
authors: Karanam
authors: K
authors: Balasubramanyam
authors: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India; and cbhas@jncasr.ac.in rangappaks@chemistry.uni-mysore.ac.in tapas@jncasr.ac.in.
authors: Rangappa Kanchugarakoppal
authors: RK
authors: Subbegowda
authors: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, cbhas@jncasr.ac.in rangappaks@chemistry.uni-mysore.ac.in tapas@jncasr.ac.in.
authors: Tapas K
authors: TK
authors: Kundu
authors: Light Scattering Laboratory, Chemistry and Physics of Materials Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India; cbhas@jncasr.ac.in rangappaks@chemistry.uni-mysore.ac.in tapas@jncasr.ac.in.
authors: Chandrabhas
authors: http://orcid.org/0000-0001-6256-8994
authors: C
authors: Narayana
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D015736:Felodipine / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015203:Reproducibility of Results; D013059:Spectrum Analysis, Raman; D064047:Spindle Poles / Q000187:drug effects / Q000378:metabolism; D013499:Surface Properties
chemical_list: D047428:Protein Kinase Inhibitors; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D015736:Felodipine
keywords: ligand binding; structure–activity relationship; vibrational spectroscopy