F Javier Luque

University of Barcelona, Barcino, Catalonia, Spain

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Publications (236)1186.4 Total impact

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    ABSTRACT: Background: Combined fatty acid amide hydrolase (FAAH) and cyclooxygenase (COX) inhibition is a promising approach for pain-relief. The Flu-AM1 and Ibu-AM5 derivatives of flurbiprofen and ibuprofen retain similar COX-inhibitory properties and are more potent inhibitors of FAAH than the parent compounds. However, little is known as to the nature of their interaction with FAAH, or to the importance of their chirality. This has been explored here. Methodology/principal findings: FAAH inhibitory activity was measured in rat brain homogenates and in lysates expressing either wild-type or FAAHT488A-mutated enzyme. Molecular modelling was undertaken using both docking and molecular dynamics. The (R)- and (S)-enantiomers of Flu-AM1 inhibited rat FAAH with similar potencies (IC50 values of 0.74 and 0.99 μM, respectively), whereas the (S)-enantiomer of Ibu-AM5 (IC50 0.59 μM) was more potent than the (R)-enantiomer (IC50 5.7 μM). Multiple inhibition experiments indicated that both (R)-Flu-AM1 and (S)-Ibu-AM5 inhibited FAAH in a manner mutually exclusive to carprofen. Computational studies indicated that the binding site for the Flu-AM1 and Ibu-AM5 enantiomers was located between the acyl chain binding channel and the membrane access channel, in a site overlapping the carprofen binding site, and showed a binding mode in line with that proposed for carprofen and other non-covalent ligands. The potency of (R)-Flu-AM1 was lower towards lysates expressing FAAH mutated at the proposed carprofen binding area than in lysates expressing wild-type FAAH. Conclusions/significance: The study provides kinetic and structural evidence that the enantiomers of Flu-AM1 and Ibu-AM5 bind in the substrate channel of FAAH. This information will be useful in aiding the design of novel dual-action FAAH: COX inhibitors.
    PLoS ONE 11/2015; 10(11):e0142711. DOI:10.1371/journal.pone.0142711 · 3.23 Impact Factor
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    Jordi Ribas · Elena Cubero · F. Javier Luque · Modesto Orozco ·

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    ABSTRACT: The structural and physicochemical properties of the adamantane nucleus account for its use as a chemical scaffold in multiple drugs. In the last years, we have developed new polycyclic scaffolds as surrogates of the adamantane group with encouraging results in multiple targets. As adamantane is a common structural feature in several 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors, we have explored the ability of the 6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethanobenzo[9]annulen-7-yl scaffold to act as a surrogate of the adamantane nucleus in a novel series of 11β-HSD1 inhibitors. Of note, within this family of compounds one derivative is endowed with submicromolar 11β-HSD1 inhibitory activity. Molecular modeling studies support the binding of the compounds to the active site of the enzyme. However, a fine tuning of the hydrophobicity of the size-expanded nucleus may be beneficial for the inhibitory potency.
    Bioorganic & medicinal chemistry 11/2015; DOI:10.1016/j.bmc.2015.11.004 · 2.79 Impact Factor
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    ABSTRACT: A unique defense mechanisms by which M. tuberculosis protects itself from nitrosative stress is based on the O2 -dependent NO dioxygenase (NOD) activity of truncated hemoglobin 2/2HbN (Mt2/2HbN). The NOD activity largely depends on the efficiency of ligand migration to the heme cavity through a two-tunnel (long and short) system; recently, it has also been correlated to the presence at the Mt2/2HbN N-terminus of a short pre-A region, not conserved in most 2/2HbNs, whose deletion results in a drastic reduction of NO scavenging. Here we present the 1.53 Å resolution crystal structure of Mt2/2HbN-ΔpreA, lacking the pre-A region. We show that removal of the pre-A region results in long range effects on the protein C-terminus, promoting the assembly of a stable dimer, both in the crystals and in solution. In the Mt2/2HbN-ΔpreA dimer access of heme ligands to the short tunnel is hindered. MD simulations show that the long tunnel branch is the only accessible pathway for O2 -ligand migration to/from the heme, and that the gating residue Phe(62)E15 partly restricts the tunnel diameter. Accordingly, kinetic measurements indicate that the kon value for peroxynitrite isomerization by Mt2/2HbN-ΔpreA -Fe(III) is 4-fold lower relative to the full-length protein, and that NO scavenging by Mt2/2HbN-ΔpreA-Fe(II)-O2 is reduced by 35-fold. Therefore, we speculate that Mt2/2HbN evolved to host the pre-A region as a mechanism to prevent dimerization, thus reinforcing survival of the microorganism against the reactive nitrosative stress in macrophages. This article is protected by copyright. All rights reserved.
    FEBS Journal 10/2015; DOI:10.1111/febs.13571 · 4.00 Impact Factor
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    ABSTRACT: Two domino Diels–Alder adducts were obtained from 3,7-bis(cyclopenta-2,4-dien-1-ylidene)-cis-bicyclo[3.3.0]octane and dimethyl acetylenedicarboxylate or N-methylmaleimide under microwave irradiation. From the first adduct, a C20H24 diene with C2v symmetry was obtained by Zn/AcOH reduction, hydrolysis, oxidative decarboxylation, and selective hydrogenation. Photochemical [2+2] cycloaddition of this diene gave a thermally unstable cyclobutane derivative, which reverts to the diene. However, both the diene and the cyclobutane derivatives could be identified by X-ray diffraction analysis upon irradiation of the diene crystal. New six-membered rings are formed upon the transannular addition of bromine or iodine to the diene. The N-type selectivity of the addition was examined by theoretical calculations, which revealed the distinct susceptibility of the doubly bonded carbon atoms to the bromine attack.
    Chemistry - A European Journal 08/2015; 21(40). DOI:10.1002/chem.201502351 · 5.73 Impact Factor
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    ABSTRACT: The adamantane scaffold is found in several marketed drugs and in many investigational 11β-HSD1 inhibitors. Interestingly, all the clinically approved adamantane derivatives are C-1 substituted. We demonstrate that, in a series of paired adamantane isomers, substitution of the adamantane in C-2 is preferred over the substitution at C-1 and is necessary for potency at human 11β-HSD1. Furthermore, the introduction of an oxygen atom in the hydrocarbon scaffold of adamantane is deleterious to 11β-HSD1 inhibition. Molecular modeling studies provide a basis to rationalize these features. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Bioorganic & medicinal chemistry letters 08/2015; 25(19). DOI:10.1016/j.bmcl.2015.07.097 · 2.42 Impact Factor
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    ABSTRACT: Recent advances in polarizable force fields have revealed that major reparameterization is necessary when the polarization energy is treated explicitly. This study is focused on the torsional parameters, which are crucial for the accurate description of conformational equilibria in biomolecules. In particular, attention is paid to the influence of polarization on the (i) transferability of dihedral terms between molecules, (ii) transferability between different environments, and (iii) additivity of dihedral energies. To this end, three polarizable force fields based on the induced point dipole model designed for use in AMBER are tested, including two recent ff02 reparameterizations. Attention is paid to the contributions due to short range interactions (1-2, 1-3, and 1-4) within the four atoms defining the dihedral angle. The results show that when short range 1-2 and 1-3 polarization interactions are omitted, as for instance in ff02, the 1-4 polarization contribution is rather small and unlikely to improve the description of the torsional energy. Conversely, when screened 1-2 and 1-3 interactions are included, the polarization contribution is sizeable and shows potential to improve the transferability of parameters between different molecules and environments as well as the additivity of dihedral terms. However, to reproduce intramolecular polarization effects accurately, further fine-tuning of the short range damping of polarization is necessary. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Journal of Computational Chemistry 07/2015; 36(25). DOI:10.1002/jcc.24012 · 3.59 Impact Factor
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    ABSTRACT: The facial selectivity of double Michael addition reactions of the silylated Nazarov reagent 4 to unsaturated indolo[2,3-a]quinolizidine lactams 3 has been studied. Pentacyclic 3-H/15-H trans adducts 5 are generated from Nind -unsubstituted lactams, but the corresponding cis isomers 6 are formed when the indole nitrogen has a tert-butyloxycarbonyl (Boc) substituent. This reversal in the facial selectivity of the annulation has been rationalized by means of theoretical calculations, which indicate that the initial nucleophilic attack under stereoelectronic control is hampered by the presence of the bulky Boc group. The synthetic usefulness of the pentacyclic Nazarov-derived adducts is demonstrated by their conversion into allo and epiallo yohimbine-type targets. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Chemistry - A European Journal 07/2015; 21(38). DOI:10.1002/chem.201501912 · 5.73 Impact Factor
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    ABSTRACT: We have synthesized a series of heptamethylene-linked levetiracetam-huprine and levetiracetam-(6-chloro)tacrine hybrids to hit amyloid, tau and cholinergic pathologies as well as β-amyloid (Aβ)-induced epileptiform activity, some of the mechanisms that eventually lead to cognitive deficits in Alzheimer's disease patients. These hybrids are potent inhibitors of human acetylcholinesterase and butyrylcholinesterase in vitro and moderately potent Aβ42 and tau anti-aggregating agents in a simple E. coli model of amyloid aggregation. Ex vivo determination of the brain acetylcholinesterase inhibitory activity of these compounds after intraperitoneal injection to C57BL6J mice has demonstrated their ability to enter the brain. The levetiracetam‒huprine hybrid 10 significantly reduced the incidence of epileptic seizures, cortical amyloid burden and neuroinflammation in APP/PS1 mice after a four-week treatment with a 5 mg/kg dose. Moreover, the hybrid 10 rescued transgenic mice from cognitive deficits, thereby emerging as an interesting disease-modifying anti-Alzheimer drug candidate.
    Journal of Medicinal Chemistry 07/2015; 58(15). DOI:10.1021/acs.jmedchem.5b00624 · 5.45 Impact Factor
  • Sònia Abás · Carolina Estarellas · F. Javier Luque · Carmen Escolano ·
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    ABSTRACT: An efficient and user-friendly synthetic process involving the combination of multicomponent reaction methodology and microwave heating generates unprecedented (2-imidazolin-4-yl)phosphonates 1–18. This strategy presents a silver-catalysed, operationally simple and environmentally friendly transformation without the need of anhydrous atmosphere or additional solvents.
    Tetrahedron 05/2015; 71(19). DOI:10.1016/j.tet.2015.03.065 · 2.64 Impact Factor
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    ABSTRACT: Cinnamic acids are present in all kinds of plant tissues and hence in herbs and derived medicines, cosmetics and foods. The interest in their role in plants and their therapeutic applications has grown exponentially. Because of their molecular structure they can exist in E- and Z-forms, which are both found in plants. However, since only the E-forms are commercially available, very few in vitro and in vivo studies of the Z-form have been reported. In this work the physico-chemical properties of Z-cinnamic acids in solution have been examined by means of UV-absorption spectroscopy and high-level quantum mechanical computations. For each isomer similar absorption spectra were obtained in methanol and acetonitrile. However, distinct trends were found for Z- and E forms of cinnamic acids in water, where a higher hypsochromic shift of the Z-isomer relative to the E-form was observed. In general the wavelength of maximal absorption of the Z-form is dramatically blue shifted (-30 to -40nm) to λ<280nm, while a slightly blue shift of the absorption maxima for the corresponding E-form (+3 to -4nm) was observed. This difference is associated with the non-planar, largely distorted, Z-structure and to the almost complete flat structure of the E-form. The results provide a basis for the study of functional and biotechnological roles of cinnamic acids and for the analysis of samples containing mixture of both geometric isomers. Copyright © 2015. Published by Elsevier B.V.
    Journal of photochemistry and photobiology. B, Biology 04/2015; 148. DOI:10.1016/j.jphotobiol.2015.03.032 · 2.96 Impact Factor
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    ABSTRACT: Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[,10).0(3,7).0(9,11)]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[,5).0(3,11).0(4,9).0(6,17).0(12,16)]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 04/2015; 96. DOI:10.1016/j.ejmech.2015.04.030 · 3.45 Impact Factor
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    ABSTRACT: Nitrophorins represent a unique class of heme proteins that are able to perform the delicate transportation and release of the free-radical gaseous messenger nitric oxide (NO) in a pH-triggered manner. Besides its ability to bind to phospholipid membranes, the N-terminus contains an additional Leu-Pro-Gly stretch, which is a unique sequence trait, and the heme cavity is significantly altered with respect to other nitrophorins. These distinctive features encouraged us to solve the X-ray crystallographic structures of NP7 at low and high pH and bound with different heme ligands (nitric oxide, histamine, imidazole). The overall fold of the lipocalin motif is well preserved in the different X-ray structures and resembles the fold of other nitrophorins. However, a chain-like arrangement in the crystal lattice due to a number of head-to-tail electrostatic stabilizing interactions is found in NP7. Furthermore, the X-ray structures also reveal ligand-dependent changes in the orientation of the heme, as well as in specific interactions between the A-B and G-H loops, which are considered to be relevant for the biological function of nitrophorins. Fast and ultrafast laser triggered ligand rebinding experiments demonstrate the pH-dependent ligand migration within the cavities and the exit route. Finally, the topological distribution of pockets located around the heme as well as from inner cavities present at the rear of the protein provides a distinctive feature in NP7, so that while a loop gated exit mechanism to the solvent has been proposed for most nitrophorins, a more complex mechanism that involves several interconnected gas hosting cavities is proposed for NP7.
    F1000 Research 02/2015; 4. DOI:10.12688/f1000research.6060.1
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    ABSTRACT: Using a combination of molecular modeling and spectroscopic experiments, the naturally occurring, pharmacologically active hypericin compound is shown to form a stable complex with the dimeric form of β-lactoglobulin (β-LG). Binding is predicted to occur at the narrowest cleft found at the interface between monomers in the dimeric β-LG. The complex is able to preserve the fluorescence and singlet oxygen photosensitizing properties of the dye. The equilibrium constant for hypericin binding has been determined as Ka = 1.40 ± 0.07 μM−1, equivalent to a dissociation constant, Kd = 0.71 ± 0.03 μM. The complex is active against Staphylococcus aureus bacteria. Overall, the results are encouraging for pursuing the potential application of the complex between hypericin and β-LG as a nanodevice with bactericidal properties for disinfection.
    Journal of Dairy Science 11/2014; 98(1). DOI:10.3168/jds.2014-8691 · 2.57 Impact Factor
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    ABSTRACT: UbcH10 is a component of the Ubiquitin Conjugation Enzymes (Ubc; E2) involved in the ubiquitination cascade controlling the cell cycle progression, whereby ubiquitin, activated by E1, is transferred through E2 to the target protein with the involvement of E3 enzymes. In this work we propose the first three dimensional model of the tetrameric complex formed by the human UbA1 (E1), two ubiquitin molecules and UbcH10 (E2), leading to the transthiolation reaction. The 3D model was built up by using an experimentally guided incremental docking strategy that combined homology modeling, protein-protein docking and refinement by means of molecular dynamics simulations. The structural features of the in silico model allowed us to identify the regions that mediate the recognition between the interacting proteins, revealing the active role of the ubiquitin crosslinked to E1 in the complex formation. Finally, the role of these regions involved in the E1-E2 binding was validated by designing short peptides that specifically interfere with the binding of UbcH10, thus supporting the reliability of the proposed model and representing valuable scaffolds for the design of peptidomimetic compounds that can bind selectively to Ubcs and inhibit the ubiquitylation process in pathological disorders.
    PLoS ONE 11/2014; 9(11):e112082. DOI:10.1371/journal.pone.0112082 · 3.23 Impact Factor
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    ABSTRACT: Predicting the conformational preferences of flexible compounds is a challenging problem in drug design, where the recognition between ligand and receptor is affected by the ability of the interacting partners to adopt a favorable conformation for the binding. In order to explore the conformational space of flexible ligands and to obtain the relative free energy of the conformation wells, we have recently reported a multilevel computational strategy that relies on the predominant-state approximation - where the conformational space is partitioned into distinct conformational wells - and combines a low-level method for sampling the conformational minima and high-level ab initio calculations for estimating their relative stability. In this study, we assess the performance of the multilevel strategy for predicting the conformational preferences of a series of structurally related phenylethylamines and streptomycin in aqueous solution. The charged nature of these compounds and the chemical complexity of streptomycin make them a challenging test for the multilevel approach. Further, we explore the suitability of using a molecular mechanics approach as a source of approximate ensembles in the first stage of the multilevel strategy. The results support the reliability of the multilevel approach for obtaining an accurate conformational ensemble of small (bio)organic molecules in aqueous solution.
    The Journal of Physical Chemistry B 10/2014; 119(3). DOI:10.1021/jp506779y · 3.30 Impact Factor
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    ABSTRACT: Myoglobin (Mb) and neuroglobin (Ngb) are representative members of pentacoordinated and bis-histidyl, hexacoordinated globins. In spite of their low sequence identity, they show surprisingly similar three-dimensional folds. The ability of Ngb to form a hexacoordinated bis-histidyl complex with the distal HisE7 has a strong impact on ligand affinity. The factors governing such different behaviors have not been completely understood yet, even though they are extremely relevant to establish structure-function relationships within the globin superfamily. In this work we generated chimeric proteins by swapping a previously identified regulatory segment - the CD region - and evaluated comparatively the structural and functional properties of the resulting proteins by molecular dynamics simulations, and spectroscopic and kinetic investigations. Our results show that chimeric proteins display heme coordination properties displaced towards those expected for the corresponding CD region. In particular, in the absence of exogenous ligands, chimeric Mb is found as a partially hexacoordinated bis-histidyl species, whereas chimeric Ngb shows a lower equilibrium constant for forming a hexacoordinated bis-histidyl species. While these results confirm the regulatory role of the CD region for bis-histidyl hexacoordination, they also suggest that additional sources contribute to fine tune the equilibrium. General significance Globins constitute a ubiquitous group of heme proteins widely found in all kingdoms of life. These findings raise challenging questions regarding the structure-function relationships in these proteins, as bis-histidyl hexacoordination emerges as a novel regulatory mechanism of the physiological function of globins. Copyright © 2014 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - General Subjects 10/2014; 1850(1). DOI:10.1016/j.bbagen.2014.10.006 · 4.38 Impact Factor
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    ABSTRACT: Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaol-huprine hybrids, purported to hit several key targets involved in Alzheimer's disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS(+), DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Aβ42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Aβ42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaol-huprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads.
    Bioorganic & Medicinal Chemistry 10/2014; 22(19). DOI:10.1016/j.bmc.2014.07.053 · 2.79 Impact Factor
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    ABSTRACT: Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O → NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5b-d have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5a-d has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Aβ42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5a-d, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities.
    European Journal of Medicinal Chemistry 07/2014; 84C:107-117. DOI:10.1016/j.ejmech.2014.07.021 · 3.45 Impact Factor
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    ABSTRACT: The α4β2 nicotinic acetylcholine receptor (nAChR) is a molecular target of 3,4-methylenedioxymethamphetamine (MDMA), a synthetic drug also known as ecstasy, and it modulates the MDMA-mediated reinforcing properties. However, the enantioselective preference of the α4β2 nAChR subtype still remains unknown. Since the two enantiomers exhibit different pharmacological profiles and stereoselective metabolism, the aim of this study is to assess a possible difference in the interaction of the MDMA enantiomers with this nAChR subtype. To this end, we report a novel simple, yet highly efficient enantioselective synthesis of the MDMA enantiomers, in which the key step is the diastereoselective reduction of imides derived from optically pure tert-butylsulfinamide. The enantioselective binding to the receptor is examined using [(3)H]epibatidine in a radioligand assay. Even though the two enantiomers induced a concentration-dependent binding displacement, (S)-MDMA has an inhibition constant 13-fold higher than (R)-MDMA, which shows a Hill's coefficient not significantly different from unity, implying a competitive interaction. Furthermore, when NGF-differentiated PC12 cells were pretreated with the compounds, a significant increase in binding of [(3)H]epibatidine was found for (R)-MDMA, indicating up-regulation of heteromeric nAChR in the cell surface. Finally, docking and molecular dynamics studies have been used to identify the binding mode of the two enantiomers, which provides a structural basis to justify the differences in affinity from the differential interactions played by the substituents at the stereogenic centre of MDMA. The results provide a basis to explore the distinct psychostimulant profiles of the MDMA enantiomers mediated by the α4β2 nAChR subtype.
    European Journal of Medicinal Chemistry 06/2014; 81:35-46. DOI:10.1016/j.ejmech.2014.04.044 · 3.45 Impact Factor

Publication Stats

7k Citations
1,186.40 Total Impact Points


  • 1993-2014
    • University of Barcelona
      • • Instituto de Biomedicina (IBUB)
      • • Department of Physical Chemistry
      • • Department of Physicochemistry
      Barcino, Catalonia, Spain
  • 2011
    • Northwestern University
      • Department of Neurobiology
      Evanston, Illinois, United States
    • Albert Einstein College of Medicine
      New York, New York, United States
  • 2009
    • Catalan Institution for Research and Advanced Studies
      Barcino, Catalonia, Spain
  • 2004
    • University of Alcalá
      Cómpluto, Madrid, Spain
  • 2003
    • Barcelona Science Park
      Barcino, Catalonia, Spain
  • 2000
    • Autonomous University of Barcelona
      • Faculty of Medicine
      Cerdanyola del Vallès, Catalonia, Spain
  • 1998
    • Universitat Ramon Llull
      Barcino, Catalonia, Spain
  • 1996
    • Institut Marqués, Spain, Barcelona
      Barcino, Catalonia, Spain