Unión fotoquímica irreversible de ligandos a albúminas séricas

Tesis por compendio[ES] En esta tesis se ha desarrollado una estrategia multidisciplinar que incluye la irradiación de complejos ligando/proteína junto con estudios de fluorescencia y/o espectroscopía de absorción transitoria, cromatografía de exclusión por tamaño seguida de espectroscopía de absorción y/o fluorescencia, análisis proteómico y modelización (docking y simulaciones de dinámica molecular) con el fin de profundizar y obtener información relevante en procesos relacionados con la formación de complejos irreversibles ligando-proteína. Ello ha permitido lograr la descripción del centro de reconocimiento molecular de albúminas séricas de distintas especies por el fármaco carprofeno, profundizar en procesos de fotoalergia producidos por el metabolito del fármaco triflusal y llevar a cabo el marcaje de residuos de lisina de la albúmina sérica humana por fotogeneración de electrófilos latentes "quinone methide". A continuación se describen brevemente cada uno de estos aspectos. En primer lugar, se ha estudiado la posible existencia de un centro de reconocimiento común en las albúminas séricas (AS) de diferentes especies empleando el fármaco antiinflamatorio no esteroideo (S)-carprofeno (CPF) como sonda fotoactiva. Así, se ha seguido la irradiación de los complejos de CPF/SA a ¿max = 320 nm por fluorescencia, mostrandose un aumento de la emisión debido a la deshalogenación. Tras la cromatografía de filtración en gel, la fracción proteica presentaba emisión proveniente del ligando, verificando la unión covalente del radical fotogenerado intermedio CBZ¿ a las AS. El análisis proteómico reveló la incorporación de CBZ¿ en varias posiciones en las diferentes albúminas. Se observaron modificaciones en la interfaz IB/IIIA en todos los casos (Tyr452 en las albúminas séricas humana, conejo y rata y Tyr451 en las albúminas séricas bovina, cerdo y oveja). Estudios de docking y de simulación de dinámica molecular el caso de albúmina sérica humana corroboraron las modificaciones covalentes observadas experimentalmente. Posteriormente, se ha investigado la unión fotoquímica del HTB, el metabolito del antiagregante plaquetario triflusal a albúmina sérica humana (ASH). El análisis proteómico de las disoluciones de HTB/ASH tras ser irradiadas mostró la adición de HTB en los grupos ¿-amino de los residuos Lys137, Lys199, Lys205, Lys352, Lys432, Lys541, Lys545 y Lys525 de la ASH. El mecanismo de reacción parece implicar la substitución del grupo CF3 del HTB por un nuevo residuo amida. Solo el residuo Lys199 se localiza en una cavidad interna de la proteína mientras que el resto de los residuos modificados resultaron estar situados en la parte externa. Los estudios computacionales revelaron que la unión supramolecular de HTB a ASH se produce en la región "V-cleft". Esta unión fotoquímica puede estar en la base de la aparición de efectos secundarios fotoalérgicos no deseados. Finalmente, se ha demostrado la utilidad de los 4-trifluorometilfenoles como pre-cursores de electrófilos latentes tipo "quinone methide" (QM) para la unión específica a residuos de lisina que se encuentran en los sitios de unión de la proteína. Así, se ha observado que estos aceptores de Michael, generados de modo fotoinducido, han sido capaces de realizar una modificación covalente específica de residuos de lisina en albúmina sérica humana (ASH). En concreto, los intermedios reactivos de tipo QM generados tras la irradiación de los complejos 4-trifluorometil-1-naftol o 4- (4-trifluorometilfenil) fenol con ASH exhibieron selectividad química hacia los residuos de lisina dando lugar a aductos de amida. Un estudio detallado realizado mediante análisis proteómico confirmó este hecho. Así, para el derivado de naftol se observó la modificación covalente de los residuos Lys106 y Lys414 (ubicados en los subdominios IA y IIIA, respectivamente), mientras que para el derivado de bife-nilol ocurrió la modificación[CA] En aquesta tesi s'ha desenvolupat una estratègia multidisciplinària que inclou la irradiació de complexos lligand/proteïna juntament amb estudis de fluorescència i/o espectroscopia d'absorció de transients, cromatografia d'exclusió de grandària se-guida d'espectroscòpia d'absorció i/o fluorescència, anàlisi i modelització proteòmica (docking i simulacions de dinàmica molecular) amb l'objectiu d'aprofundir i obtenir informació rellevant en els processos relacionats amb la formació de com-plexos lligand-proteïna irreversibles. Això ha permès la descripció del centre de reconeixement molecular d'albúmines sèriques de diferents espècies pel fàrmac carprofen, i aprofundir en processos de fotoal·lèrgia produïts pel metabolit del fàrmac triflusal i realitzar el marcatge de residus de lisina d'albúmina sèrica humana per fotogeneració d'electròfil "quinone methide" latent. Cadascun d'aquests aspectes es descriu breument a continuació. En primer lloc, s'ha estudiat la possible existència d'un centre de reconeixement comú en albúmines sèriques (AS) de diferents espècies utilitzant el fàrmac antiinflamatori no esteroïdal (S)-carprofèn (CPF) com a sonda fotoactiva. Així, s'ha se-guit la irradiació dels complexos de CPF/SA a un màxim de 320 nm per fluorescència, amb un augment de les emissions a causa de la deshalogenació. Després de la cromatografia de filtració de gel, la fracció de proteïna presentava emissió del lli-gand, verificant la unió covalent del radical fotogenerat intermedi CBZ¿ a les AS. L'anàlisi proteòmica va revelar la incorporació de CBZ¿ en diverses posicions en els diferents albúmines. En tots els casos s'han observat modificacions a la interfície IB/IIIA (Tyr452 en albúmina sèrica humana, conill i rata i Tyr451 en albúmines sèriques bovina, porc i ovella). Els estudis de docking i de simulació de dinàmiques moleculars en el cas d'albúmina sèrica humana van corroborar les modificacions covalents experimentalment observades. Posteriorment, s'ha investigat la unió fotoquímica del HTB, el metabòlit de l'antiagregant plaquetari triflusal a l'albúmina sèrica humana (ASH). L'anàlisi proteòmica de les solucions HTB/ASH després de ser irradiades mostraren l'addició de HTB en els grups ¿-amino dels residus Lys137, Lys199, Lys205, Lys352, Lys432, Lys541, Lys545 i Lys525 de la ASH . El mecanisme de reacció podria implicar la substitució del grup CF3 de la HTB amb un nou residu d'amida. Només el residu Lys199 està situat en una cavitat interna de la proteïna, mentre que la resta dels residus modificats van resultar estar situats a l'exterior. Els estudis computacionals van revelar que la unió supramolecular de HTB a ASH es produeix a la regió "V-cleft". Aquesta unió fotoquímica pot ser la base de l'aparició d'efectes secundaris fotoal·lèrgics no desitjats. Finalment, s'ha demostrat la utilitat de 4-trifluorometilfenols com a precursors d'electròfils latents "quinone methide" (QM) per a la unió específica a residus de lisina trobats en els llocs d'unió de la proteïna. Per tant, s'ha observat que els acceptors de Michael, generats de manera foto-induïda han pogut fer una modificació covalent específica de residus de lisina en albúmina de sèrica humana (ASH). Concretament, els intermedis reactius del tipus QM generats després de la irradiació dels complexos 4-trifluoromethyl-1-naftol o 4-(4-trifluoromethylphenyl) fenol amb ASH exhibiren selectivitat química als residus de lisina resultant en aductes ami-da. Un estudi detallat realitzat mitjançant anàlisi proteòmica confirmà aquest fet. Així, pel derivat del naftol, es va observar la modificació covalents de residus Lys106 i Lys414 (localitzada en subdominis IA i IIIA, respectivament), mentre que per al derivat de bifenil la modificació es va produir en el Lys195 (en subdomini IIA). Els estudis teòrics proporcionen una visió molecular més profunda de la selectivitat observada[EN] In this thesis a multidisciplinary strategy has been developed that includes irradiation of ligand/protein complexes along with fluorescence and/or transient absorption spectroscopy, size-exclusion chromatography followed by absorption and/or fluorescence spectroscopy, proteomic analysis and modelling (docking and molecular dynamics simulations) in order to deepen and obtain relevant information in processes related to the formation of irreversible ligand-protein complexes. This has made it possible to achieve the description of the molecular recognition centre of serum albumin of different species by the carprofen drug, to deepen in photoallergy processes produced by the metabolite of the triflusal drug and to carry out the la-belling of lysine residues of human serum albumin by photogeneration of latent electrophiles "quinone methide". Each of these aspects is briefly described below. First, the possible existence of a common recognition centre in serum albumin (SA) of different species has been studied using the non-steroidal antiinflammatory drug (S)-carprofen (CPF) as a photoactive probe. Thus, irradiation of the CPF/SA complexes at ¿max = 320 nm has been followed by fluorescence, showing an increase in emission due to dehalogenation. After gel filtration chromatography, the protein fraction presented emission from the ligand, verifying the covalent bonding of the CBZ¿ intermediate photogenerated radical to the SA. Proteomic analysis revealed the incorporation of CBZ¿ in various positions in the different albumins. Modifications in the IB/IIIA interface were observed in all cases (Tyr452 in human, rabbit and rat serum albumin and Tyr451 in bovine, porcine and sheep serum albumin). Docking and molecular dynamics simulation studies in the case of human serum albumin corroborated the experimentally observed covalent modifications. Subsequently, the photochemical binding of HTB, the metabolite of the triflusal platelet antiaggregant to human serum albumin (HSA), has been investigated. Proteomic analysis of the HTB/HSA solutions after being irradiated showed the addition of HTB in the ¿-amino groups of residues Lys137, Lys199, Lys205, Lys352, Lys432, Lys541, Lys545 and Lys525 of the HSA. The reaction mechanism seems to involve replacing the CF3 group of HTB with a new amide residue. Only the Lys199 residue is located in an internal cavity of the protein whilst the rest of the modified residues were found to be located on the outside. Computational studies revealed that supramolecular binding of HTB to HSA occurs in the "V-cleft" region. This photochemical binding may be at the base of the appearance of unwanted photoallergic side effects. Finally, the utility of 4-trifluoromethylphenols as precursors of latent "quinone methide" (QM) type electrophiles for specific binding to lysine residues found at the protein binding sites has been demonstrated. Thus, it has been observed that these photogenerated Michael acceptors, have been able to perform a specific covalent modification of lysine residues in human serum albumin (HSA). Specifically, the QM type reactive intermediates generated after irradiation of the 4-trifluoromethyl-1-naphthol or 4- (4-trifluoromethylphenyl) phenol complexes with HSA exhibited chemical selectivity towards lysine residues giving rise to amide adducts. A detailed study conducted by proteomic analysis confirmed this fact. Thus, for the naphthol derivative the covalent modification of residues Lys106 and Lys414 (located in subdomains IA and IIIA, respectively) was observed, while for the biphenyl derivative the modification occurred in Lys195 (in subdomain IIA). Theoretical studies provided a deeper insight at the molecular level of the experimentally observed selectivity.Molins Molina, Ó. (2020). Unión fotoquímica irreversible de ligandos a albúminas séricas [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/139676TESISCompendi

Photogeneration of Quinone Methides as Latent Electrophiles for Lysine Targeting

[EN] Latent electrophiles are nowadays very attractive chemical entities for drug discovery, as they are unreactive unless activated upon binding with the specific target. In this work, the utility of 4-trifluoromethyl phenols as precursors of latent electrophiles, quinone methides (QM), for lysine-targeting is demonstrated. These Michael acceptors were photogenerated for specific covalent modification of lysine residues using human serum albumin (HSA) as a model target. The reactive QM-type intermediates I or II, generated upon irradiation of 4-trifluoromethyl-1-naphthol (1)@HSA or 4-(4-trifluorometylphenyl)phenol (2)@HSA complexes, exhibited chemoselective reactivity toward lysine residues leading to amide adducts, which was confirmed by proteomic analysis. For ligand 1, the covalent modification of residues Lys106 and Lys414 (located in subdomains IA and IIIA, respectively) was observed, whereas for ligand 2, the modification of Lys195 (in subdomain IIA) took place. Docking and molecular dynamics simulation studies provided an insight into the molecular basis of the selectivity of 1 and 2 for these HSA subdomains and the covalent modification mechanism. These studies open the opportunity of performing protein silencing by generating reactive ligands under very mild conditions (irradiation) for specific covalent modification of hidden lysine residues.Financial support from the Spanish Ministry of Economy and Competiveness [CTQ2016-78875-P, SAF2016-75638-R and BES-2014-069404 (predoctoral fellowship to O.M.-M.)], the Generalitat Valenciana (PROMETEO/2017/075), the Community of Madrid (2016-T1/AMB-1275), the Xunta de Galicia (Centro Singular de Investigacion de Galicia accreditation 2016-2019, ED431G/09 and postdoctoral fellowship to E.L.), and the European Union (European Regional Development Fund, ERDF) is gratefully acknowledged. 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. We are grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae computer.Pérez Ruiz, R.; Molins-Molina, O.; Lence, E.; González-Bello, C.; Miranda Alonso, MÁ.; Jiménez Molero, MC. (2018). Photogeneration of Quinone Methides as Latent Electrophiles for Lysine Targeting. The Journal of Organic Chemistry. 83(21):13019-13029. https://doi.org/10.1021/acs.joc.8b01559S1301913029832

Smart Beam Management for Vehicular Networks Using ML

[EN] The mmWave frequencies will be widely used in future vehicular communications. At these frequencies, the radio channel becomes much more vulnerable to slight changes in the environment like motions of the device, reflections or blockage. In high mobility vehicular communications the rapidly changing vehicle environments and the large overheads due to frequent beam training are the critical disadvantages in developing these systems at mmWave frequencies. Hence, smart beam management procedures are desired to establish and maintain the radio channels. In this paper, we propose that using the positions and respective velocities of the vehicles in the dynamic selection of the beam pair, and then adapting to the changing environments using ML algorithms, can improve both network performance and communication stability in high mobility vehicular communications.This work was supported by the Spanish Comision Interministerial de Ciencia y Tecnologia (CICYT) under projects TEC2016-78028-C3-1-P and MDM2016-O6OO, Catalan Research Group 2017 SGR 21, and Industrial Doctorate programme (2018-DI-084) of Generalitat de Catalunya.Bharath-Reddy, G.; Montero, L.; Perez-Romero, J.; Molins-Benlliure, J.; Ferrando Bataller, M.; Molina, J.; Romeu, J.... (2021). Smart Beam Management for Vehicular Networks Using ML. Íñigo Cuiñas Gómez. 1-4. http://hdl.handle.net/10251/1910661

Protein binding of lapatinib and its N- and O-dealkylated metabolites interrogated by fluorescence, ultrafast spectroscopy and molecular dynamics simulations

[EN] Lapatinib (LAP) is an anticancer drug generally used to treat breast and lung cancer. It exhibits hypersensitivity reactions in addition to dermatological adverse effects and photosensitivity. Moreover, LAP binds to serum proteins and is readily biotransformed in humans, giving rise to several metabolites, such as N- and O-dealkylated products (N-LAP and O-LAP, respectively). In this context, the aim of the present work is to obtain key information on drug@protein complexation, the first step involved in a number of hypersensitivity reactions, by a combination of fluorescence, femtosecond transient absorption spectroscopy and molecular dynamics (MD) simulations. Following this approach, the behavior of LAP and its metabolites has been investigated in the presence of serum proteins, such as albumins and alpha(1)-acid glycoproteins (SAs and AGs, respectively) from human and bovine origin. Fluorescence results pointed to a higher affinity of LAP and its metabolites to human proteins; the highest one was found for LAP@HSA. This is associated to the coplanar orientation adopted by the furan and quinazoline rings of LAP, which favors emission from long-lived (up to the ns time-scale) locally-excited (LE) states, disfavoring population of intramolecular charge transfer (ICT) states. Moreover, the highly constrained environment provided by subdomain IB of HSA resulted in a frozen conformation of the ligand, contributing to fluorescence enhancement. Computational studies were clearly in line with the experimental observations, providing valuable insight into the nature of the binding sites and the conformational arrangement of the ligands inside the protein cavities. Besides, a good correlation was found between the calculated binding energies for each ligand@protein complex and the relative affinities observed in competition experiments.Financial support from the Spanish Government (RYC-201517737, CTQ2017-89416-R, SAF2016-75638-R ISCIII grants RETICS ARADyAL (RD16/0006/0004 and RD16/0006/0001), PI16/01877 and CPII16/00052), Conselleria d'Educacio Cultura i Esport (PROMETEO/2017/075), the Xunta de Galicia [ED431B 2018/04 and Centro singular de investigacion de Galicia accreditation 2019-2022 (ED431G 2019/03)] and the European Regional Development Fund is gratefully acknowledged.Andreu Ros, MI.; Lence, E.; González-Bello, C.; Mayorga, C.; Cuquerella Alabort, MC.; Vayá Pérez, I.; Miranda Alonso, MÁ. (2020). Protein binding of lapatinib and its N- and O-dealkylated metabolites interrogated by fluorescence, ultrafast spectroscopy and molecular dynamics simulations. 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