Identification of a common recognition center for a photoactive non-steroidal antiinflammatory drug in serum albumins of different species
| Autor: | Concepción González-Bello, Oscar Molins-Molina, Miguel A. Miranda, M. Consuelo Jiménez, Emilio Lence, Daniel Limones-Herrero |
|---|---|
| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Generalitat Valenciana |
| Rok vydání: | 2018 |
| Předmět: |
Fluorophore
010405 organic chemistry Stereochemistry Organic Chemistry Photodissociation Size-exclusion chromatography 010402 general chemistry 01 natural sciences Non steroidal 0104 chemical sciences A-site chemistry.chemical_compound Molecular dynamics QUIMICA ORGANICA chemistry Covalent bond Docking (molecular) QUIMICA ANALITICA 03.- Garantizar una vida saludable y promover el bienestar para todos y todas en todas las edades |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia |
| ISSN: | 2052-4129 |
| Popis: | [EN] The non-steroidal anti-inflammatory drug (S)-carprofen (CPF) has been used as a photoactive probe to investigate the possible existence of a common recognition center in serum albumins (SAs) of different species. The methodology involves irradiation of the CPF/SA complexes, coupled with gel filtration chromatography or proteomic analysis of the photolysates, docking and molecular dynamics simulations. Photolysis of CPF/SA complexes at = 320 nm, and gel filtration chromatography, revealed that the protein fraction still contained the drug fluorophore, in agreement with covalent attachment of the photogenerated radical intermediate CBZ to SAs. After trypsin digestion and ESI-MS/MS, the incorporation of CBZ was detected at several positions in the different albumins. Remarkably, modifications at the IB/IIIA interface were observed in all cases (Tyr452 in HSA, RbSA and RtSA and Tyr451 in BSA, PSA and SSA). The molecular basis of this common recognition, studied by docking and molecular dynamics simulation studies on the corresponding non-covalent complexes, corroborated the experimentally observed covalent modifications. Our computational studies also revealed that the previously reported displacement of CPF by (S)-ibuprofen, a site II specific drug, would be due to an allosteric effect in site II, rather than a direct molecular displacement, as expected. Financial support from the Spanish Ministry of Economy and Competiveness (CTQ2016-78875-P, SAF2016-75638-R and BES-2014-069404), Generalitat Valenciana (PROMETEO2017/075), Conselleria de Cultura, Educacion e Ordenacion Universitaria (Centro singular de investigacion de Galicia accreditation 2016-2019, ED431G/09) and the European Regional Development Fund (ERDF) is acknowledged. This work was also supported by Instituto de Salud Carlos III (ISCIII) co-funded by Fondo Europeo de Desarrollo Regional FEDER for the Thematic Networks and Co-operative Research Centres: ARADyAL (RD16/0006/0030). EL thanks the Xunta de Galicia for his postdoctoral fellowship. We are also grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae II supercomputer. The proteomic analysis was performed in the proteomics facility of SCSIE University of Valencia that belongs to ProteoRed PRB2-ISCIII and is supported by grant PT13/0001, of the PE I+D+I 2013-2016, funded by ISCIII and FEDER. |
| Databáze: | OpenAIRE |
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