Federico Gago

University of Alcalá, Cómpluto, Madrid, Spain

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Publications (181)705.5 Total impact

  • In Silico Drug Discovery and Design, 08/2015: pages 99-121; , ISBN: 978-1-4822-1783-4
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    ABSTRACT: Acyclic nucleoside phosphonates incorporating 2,4-diaminotriazine (DAT) as a 5-aza-analogue of the 2,4-diamino-pyrimidine (DAPym) nucleobase present in PMEO-DAPyms have been synthesized. The lead PMEO-DAT is as inhibitory against HIV, HBV, MSV and VZV replication as the parent PMEO-DAPym and equally inefficient at markedly affecting replication of HSV-1, HSV-2 and HCMV. A rationale for this similar biological profile is proposed on the basis of structural differences in the active site of the viral DNA polymerases. PMEO-DAT is, however, more selective because, unlike PMEO-DAPym, it does not stimulate secretion of β-chemokines in cultured PBMC. Copyright © 2015. Published by Elsevier B.V.
    Antiviral research 08/2015; 122. DOI:10.1016/j.antiviral.2015.08.006 · 3.94 Impact Factor
  • Current Organic Chemistry 08/2015; 19(999):1-1. DOI:10.2174/1385272819666150810213115 · 2.16 Impact Factor
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    ABSTRACT: Galactitol-1-phosphate 5-dehydrogenase (GPDH) is a polyol dehydrogenase that belongs to the medium-chain dehydrogenase/reductase (MDR) superfamily. It catalyses the Zn 2+ - and NAD + -dependent stereoselective dehydrogenation of L-galactitol 1-phosphate to D-tagatose 6-phosphate. Here, three crystal structures of GPDH from Escherichia coli are reported: that of the open state of GPDH with Zn 2+ in the catalytic site and those of the closed state in complex with the polyols Tris and glycerol, respectively. The closed state of GPDH reveals no bound cofactor, which is at variance with the conformational transition of the prototypical mammalian liver alcohol dehydrogenase. The main intersubunit-contacting interface within the GPDH homodimer presents a large internal cavity that probably facilitates the relative movement between the subunits. The substrate analogue glycerol bound within the active site partially mimics the catalytically relevant backbone of galactitol 1-phosphate. The glycerol binding mode reveals, for the first time in the polyol dehydrogenases, a pentacoordinated zinc ion in complex with a polyol and also a strong hydrogen bond between the primary hydroxyl group and the conserved Glu144, an interaction originally proposed more than thirty years ago that supports a catalytic role for this acidic residue.
    Acta Crystallographica Section D Biological Crystallography 07/2015; 71:1540-1554. DOI:10.1107/S1399004715009281 · 2.67 Impact Factor
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    ABSTRACT: All-hydrocarbon and lactam-bridged staples linking amino acid side-chains have been used to stabilize the α-helical motif in short 13-mer peptides that target critical protein-protein interactions at the dimerization interface of Leishmania infantum trypanothione reductase (Li-TryR). The design of the best positions for covalent hydrocarbon closure relied on a theoretical prediction of the degree of helicity of the corresponding cyclic peptides in water. Selected (i, i+4) and (i, i+7) hydrocarbon-stapled peptides were prepared by using solid-phase synthesis protocols and optimized ring-closing metathesis reactions under microwave conditions. Structural analysis by NMR spectroscopy confirmed high helical contents in aqueous TFE solutions for both types of helix-constrained cyclic peptides. Remarkably, the ability to reduce Li-TryR dimerization was reduced in both (i, i+4) and (i, i+7) hydrocarbon stapled peptides but was retained in the corresponding (i, i+4) Glu-Lys lactam-bridged analogue which also showed a higher resistance to proteolytic degradation by proteinase K relative to the linear peptide prototype. In silico studies indicated that the introduction of a hydrocarbon staple vs a lactam bridge likely perturbs critical interactions required for proper binding of the peptide to the Li-TryR monomer.
    RSC Advances 06/2015; 5(69). DOI:10.1039/C5RA06853C · 3.84 Impact Factor
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    Dataset: gCOMBINE
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    ABSTRACT: We present a new protocol aimed at the structure-based design of drug-like molecules using a fragment approach. It starts from a suitably placed and well-defined "base fragment" and then uses an incremental construction algorithm and a scoring function to grow the molecule into prioritized candidates. The selection of the most promising solutions for synthesis and validation is guided by the optimization of the calculated ligand efficiency indices known as binding efficiency index (BEI) and surface efficiency index (SEI), which allow the user to navigate proficiently in chemico-biological space. A test case for the protocol is exemplified here using published data for inhibitors of protein kinase B, aka AKT, a key enzyme in several signal transduction pathways. Our procedure was able to identify the main features responsible for the binding of inhibitors and guided the selection process towards molecules that included or resembled those shown as the most active in the original studies.
    Methods in molecular biology (Clifton, N.J.) 02/2015; 1289:89-100. DOI:10.1007/978-1-4939-2486-8_8 · 1.29 Impact Factor
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    ABSTRACT: Hybrids of vinca alkaloids and phomopsin A, linked by a glycine pattern, have been synthetized in one or two steps, by an original insertion reaction. These compounds have been elaborated in order to interact with both “vinca site” and “peptide site” of the vinca domain in tubulin. Two out of three hybrids are potent inhibitors of microtubules assembly and they present good cytotoxicity against different cell lines. Molecular modelling studies show they could bind, within the vinca domain, in similar spatial regions as that of vinca and phomopsin thanks to the flexibility provided by the glycine linker used to elaborate these hybrids.
    Organic & Biomolecular Chemistry 01/2015; 13(10). DOI:10.1039/C4OB02114B · 3.56 Impact Factor
  • European Journal of Cancer 11/2014; 50:108. DOI:10.1016/S0959-8049(14)70460-5 · 5.42 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):5467-5467. DOI:10.1158/1538-7445.AM2014-5467 · 9.33 Impact Factor
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    ABSTRACT: Hybrids of vinca alkaloids and phomopsin A have been elaborated with the aim of interfering with both the "vinca site" and the "peptide site" of the so-called vinca domain in tubulin. They were synthesized by an efficient one-pot procedure that links directly the octahydrophomopsin lateral chain to the velbenamine moiety of 7'-homo-anhydrovinblastine. In their modeled complexes with tubulin, these hybrids were found to superimpose nicely on the tubulin-bound structures of vinblastine and phomopsin A. This good matching can account for the fact that two of them are very potent inhibitors of microtubule assembly and display good cytotoxicity against four cancer cell lines.
    Journal of Medicinal Chemistry 05/2014; 57(12). DOI:10.1021/jm500530v · 5.45 Impact Factor
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    ABSTRACT: A series of novel thienopyrimidin-4-amines have been synthesized and evaluated as phosphodiesterase (PDE) inhibitors. A rationale for the observed selectivity against PDE7 has been obtained from molecular modelling studies on the most active compounds.
    Organic & Biomolecular Chemistry 05/2014; 12(24). DOI:10.1039/c4ob00175c · 3.56 Impact Factor
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    ABSTRACT: Mycoplasmas are opportunistic parasites and some species are suggested to preferentially colonize tumor tissue in cancer patients. We could demonstrate that the annotated thymidine phosphorylase (TP) gene in the genome of Mycoplasma hyorhinis encodes a pyrimidine nucleoside phosphorylase (PyNPHyor) that not only efficiently catalyzes thymidine but also uridine phosphorolysis. The kinetic characteristics of PyNPHyor-catalyzed nucleoside and nucleoside analogue (NA) phosphorolysis were determined. We demonstrated that the expression of such an enzyme in mycoplasma-infected cell cultures dramatically alters the activity of various anticancer/antiviral NAs such as 5-halogenated pyrimidine nucleosides, including 5-trifluorothymidine (TFT). Due to their close association with human cancers, the presence of mycoplasmas may markedly influence the therapeutic efficiency of nucleoside-based drugs.
    Nucleosides Nucleotides &amp Nucleic Acids 04/2014; 33(4-6):394-402. DOI:10.1080/15257770.2013.851394 · 1.02 Impact Factor
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    ABSTRACT: The genome of the lactic acid bacterium Lactobacillus plantarum WCFS1 reveals the presence of a rich repertoire of esterases and lipases highlighting their important role in cellular metabolism. Among them is the carboxylesterase LpEst1 a bacterial enzyme related to the mammalian hormone-sensitive lipase, which is known to play a central role in energy homeostasis. In this study, the crystal structure of LpEst1 has been determined at 2.05 Å resolution; it exhibits an αβ-hydrolase fold, consisting of a central β-sheet surrounded by α-helices, endowed with novel topological features. The structure reveals a dimeric assembly not comparable with any other enzyme from the bacterial hormone-sensitive lipase family, probably echoing the specific structural features of the participating subunits. Biophysical studies including analytical gel filtration and ultracentrifugation support the dimeric nature of LpEst1. Structural and mutational analyses of the substrate-binding pocket and active site together with biochemical studies provided insights for understanding the substrate profile of LpEst1 and suggested for the first time the conserved Asp173, which is adjacent to the nucleophile, as a key element in the stabilization of the loop where the oxyanion hole resides.
    PLoS ONE 03/2014; 9(3):e92257. DOI:10.1371/journal.pone.0092257 · 3.23 Impact Factor
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    ABSTRACT: EndoG, a member of the DNA/RNA non-specific ββα-metal family of nucleases, has been demonstrated to be present in many organisms, including Trypanosomatids. This nuclease participates in the apoptotic program in these parasites by migrating from the mitochondrion to the nucleus, where it takes part in the degradation of genomic DNA that characterizes this process. We now demonstrate that Leishmania infantum EndoG (LiEndoG) is an endo-exonuclease that has a preferential 5' exonuclease activity on linear DNA. Regardless of its role during apoptotic cell death, this enzyme seems to be necessary during normal development of the parasites as indicated by the reduced growth rates observed in LiEndoG hemi-knockouts and their poor infectivity in differentiated THP-1 cells. The pro-life role of this protein is also corroborated by the higher survival rates of parasites that over-express this protein after treatment with the LiEndoG inhibitor Lei49. Taken together, our results demonstrate that this enzyme plays essential roles in both survival and death of Leishmania parasites.
    PLoS ONE 02/2014; 9(2):e89526. DOI:10.1371/journal.pone.0089526 · 3.23 Impact Factor
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    ABSTRACT: The binding of epothilones to dimeric tubulin and to microtubules has been studied by means of biochemical and NMR techniques. We have determined the binding constants of epothilone A (EpoA) and B (EpoB) to dimeric tubulin, which are four orders of magnitude lower than those for microtubules, and we have elucidated the conformation and binding epitopes of EpoA and EpoB when bound to tubulin dimers and microtubules in solution. The determined conformation of epothilones when bound to dimeric tubulin is similar to that found by X-ray crystallographic techniques for the binding of EpoA to the Tubulin/RB3/TTL complex; it is markedly different from that reported for EpoA bound to zinc-induced sheets obtained by electron crystallography. Likewise, only the X-ray structure of EpoA bound to the Tubulin/RB3/TTL complex at the luminal site, but not the electron crystallography structure, is compatible with the results obtained by STD on the binding epitope of EpoA bound to dimeric tubulin, thus confirming that the allosteric change (structuring of the M-loop) is the biochemical mechanism of induction of tubulin assembly by epothilones. TR-NOESY signals of EpoA bound to microtubules have been obtained supporting the interaction with a transient binding site with a fast exchange rate (pore site), consistent with the notion that epothilones access the luminal site through the pore site, as has also been observed for taxanes. Finally, the differences in the tubulin binding affinities of a series of epothilone analogs has been quantitatively explained using the newly determined binding pose and the COMBINE methodology.
    ACS Chemical Biology 02/2014; 9(4). DOI:10.1021/cb400673h · 5.33 Impact Factor
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    ABSTRACT: The type II dehydroquinase (DHQ2), which is an essential enzyme in Helicobacter pylori and Mycobacterium tuberculosis, is recognized to be an attractive target for the development of new antibacterial agents. Computational and biochemical studies that help understand in atomic detail the catalytic mechanism these bacterial enzymes are reported. Asp89*/Asp88* from a symmetry-related neighboring enzyme subunit proved to be the residue responsible for the deprotonation of the essential tyrosine to afford the catalytic tyrosinate, which triggers the enzymatic process. The essentiality of this residue is supported by results from site-directed mutagenesis. For H. pylori DHQ2, this reaction takes place through the assistance of a water molecule, while for M. tuberculosis DHQ2, the tyrosine is directly deprotonated by the aspartate residue. The participation of a water molecule in this deprotonation reaction is supported by solvent isotope effects and proton inventory studies. Molecular dynamics simulation studies provide details of the required motions for the catalytic turnover, which provides a complete overview of the catalytic cycle. The product is expelled from the active site by the essential arginine and after a large conformational change of a loop containing two conserved arginines (Arg109/Arg108 and Arg113/Arg112), which reveals a previously unknown key role of these residues. The new insights can be used to advantage in the structure-based design of novel inhibitors.
    Biochemical Journal 01/2014; 458(3). DOI:10.1042/BJ20131103 · 4.40 Impact Factor
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    ABSTRACT: ALFA is a fast computational tool for the conformational analysis of small molecules that uses a custom-made iterative algorithm to provide a set of representative conformers in an attempt to reproduce the diversity of states in which small molecules can exist, either isolated in solution or bound to a target. The results shown in this work prove that ALFA is fast enough to be integrated into massive high-throughput virtual screening protocols with the aim of incorporating ligand flexibility and also that ALFA reproduces crystallographic X-ray structures of bound ligands with great accuracy. Furthermore, the application includes a graphical user interface that allows its use through the popular molecular graphics program PyMOL to make it accessible to non-expert users. ALFA is distributed free of charge upon request from the authors.
    Journal of Chemical Information and Modeling 01/2014; 54(1). DOI:10.1021/ci400453n · 3.74 Impact Factor
  • Ajikumar Parayil · Federico Gago
    Current Opinion in Biotechnology 10/2013; 24(6). DOI:10.1016/j.copbio.2013.10.001 · 7.12 Impact Factor
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    ABSTRACT: We have previously shown that cells deficient in the Fanconi anemia (FA) pathway are hypersensitive to trabectedin, a DNA-binding anticancer tetrahydroisoquinoline (DBAT) whose adducts functionally mimic a DNA inter-strand crosslink (ICL). Now we expand our observations to new DBATs and investigate whether our findings in primary untransformed cells can be reproduced in human cancer cells. The sensitivity of FA-competent and FA-deficient transformed and untransformed cells to mitomycin C (MMC) and to three DBATs, trabectedin, Zalypsis and PM01183, was first assessed. Additionally, the functional interaction of these drugs with the FA pathway was comparatively investigated. While untransformed FA-deficient hematopoietic cells were hypersensitive to both MMC and DBATs, the response of FA-deficient squamous cell carcinoma (SCC) cells to DBATs was similar to that of their respective FA-competent counterparts, even though these FA-deficient SCC cells showed the expected hypersensitivity to MMC. Furthermore, while MMC always activated the FA pathway, DBATs inhibited FA pathway in the cancer cell lines tested and this enhanced their response to MMC. Taken together, our data show that although DBATs may functionally interact with DNA like agents that generate classical ICL, these drugs should be considered as FA pathway inhibitors, rather than activators. Moreover, this effect was most significant in a variety of cancer cells. We propose that the inhibitory effects of DBATs on the FA pathway could be exploited clinically with the aim of "fanconizing" cancer cells in order to make them more sensitive to other antitumor drugs.
    British Journal of Pharmacology 08/2013; 170(4). DOI:10.1111/bph.12331 · 4.84 Impact Factor

Publication Stats

3k Citations
705.50 Total Impact Points


  • 1986–2015
    • University of Alcalá
      • • Department of Biomedical Sciences II
      • • Department of Organic and Inorganic Chemistry
      Cómpluto, Madrid, Spain
  • 2014
    • Spanish National Research Council
      Madrid, Madrid, Spain
  • 2013
    • Manus Biosynthesis
      Cambridge, Massachusetts, United States
  • 1987–2012
    • Hospital Universitario Henares
      Madrid, Madrid, Spain
  • 2001–2010
    • University of Leuven
      • Department of Biomedical Kinesiology
      Louvain, Flemish, Belgium
  • 2005
    • University of Rome Tor Vergata
      Roma, Latium, Italy
  • 2004
    • Georgia State University
      • Department of Chemistry
      Atlanta, Georgia, United States
  • 1994–2004
    • University of Barcelona
      • Departament de Fisicoquímica
      Barcelona, Catalonia, Spain
  • 2003
    • Universidad del País Vasco / Euskal Herriko Unibertsitatea
      • Departamento de Química Orgánica I
      San Sebastián, Basque Country, Spain
  • 1989
    • University of Oxford
      • Physcial and Theoretical Chemistry Laboratory
      Oxford, England, United Kingdom