Santiago Garcia-Vallvé

Publications of Santiago Garcia-Vallvé

• DecoyFinder: an easy-to-use python GUI application for building target-specific decoy sets.

  Authors: Adrià Cereto-Massagué, Laura Guasch, Cristina Valls, Miquel Mulero, Gerard Pujadas, Santiago Garcia-Vallvé

  Bioinformatics (Oxford, England). 04/2012;

  SUMMARY: Decoys are molecules that are presumed to be inactive against a target (i.e., will not likely bind to the target) and are used to validate the performance of molecular docking or a virtualSUMMARY: Decoys are molecules that are presumed to be inactive against a target (i.e., will not likely bind to the target) and are used to validate the performance of molecular docking or a virtual screening workflow. The DUD database (http://dud.docking.org/) provides a free directory of decoys for use in virtual screening, though it only contains a limited set of decoys for 40 targets.To overcome this limitation, we have developed an application called DecoyFinder that selects, for a given collection of active ligands of a target, a set of decoys from a database of compounds. Decoys are selected if they are similar to active ligands according to five physical descriptors (molecular weight, number of rotational bonds, total hydrogen bond donors, total hydrogen bond acceptors and the octanol-water partition coefficient) without being chemically similar to any of the active ligands used as an input (according to the Tanimoto coefficient between MACCS fingerprints). To the best of our knowledge, DecoyFinder is the first application designed to build target-specific decoy sets. AVAILABILITY: DecoyFinder is freely available at http://URVnutrigenomica-CTNS.github.com/DecoyFinder CONTACT: santi.garcia-vallve@urv.cat SUPPLEMENTARY INFORMATION: A complete description of the software is included on the application home page. A validation of DecoyFinder on 10 DUD targets is provided as supplementary table1.

• Development of docking-based 3D-QSAR models for PPARgamma full agonists.

  Authors: Laura Guasch, Esther Sala, Cristina Valls, Miquel Mulero, Gerard Pujadas, Santiago Garcia-Vallvé

  Journal of molecular graphics & modelling. 03/2012; 36C:1-9.

  Peroxisome proliferator-activated receptor gamma (PPARγ) has become an attractive molecular target for drugs that aim to treat diabetes mellitus type II, and its therapeutic potency against skinPeroxisome proliferator-activated receptor gamma (PPARγ) has become an attractive molecular target for drugs that aim to treat diabetes mellitus type II, and its therapeutic potency against skin cancer and other skin diseases is also currently being explored. To study the relationship between the structure of several PPARγ full agonists and the trans-activation activity of PPARγ, we have performed a three-dimensional quantitative structure-activity relationship (3D-QSAR) study of tyrosine-based derivatives, based on the 3D alignment of conformations obtained by docking. Highly predictive 3D-QSAR models, with Pearson-R values of 0.86 and 0.90, were obtained for the transactivation activity and binding affinity of PPARγ, respectively. These models are in good agreement with the structural characteristics of the binding pocket of PPARγ and provide some structural insights for the improvement of PPARγ full agonist bioactivities.

• Identification of human IKK-2 inhibitors of natural origin (Part II): in Silico prediction of IKK-2 inhibitors in natural extracts with known anti-inflammatory activity.

  Authors: Esther Sala, Laura Guasch, Justyna Iwaszkiewicz, Miquel Mulero, Maria-Josepa Salvadó, Cinta Bladé, Meritxell Ceballos, Cristina Valls, Vincent Zoete, Aurélien Grosdidier, Santiago Garcia-Vallvé, Olivier Michielin, Gerard Pujadas

  European journal of medicinal chemistry. 12/2011; 46(12):6098-103.

  Human inhibitor NF-κB kinase 2 (hIKK-2) is the primary component responsible for activating NF-κB in response to various inflammatory stimuli. Thus, synthetic ATP-competitive inhibitors for hIKK-2Human inhibitor NF-κB kinase 2 (hIKK-2) is the primary component responsible for activating NF-κB in response to various inflammatory stimuli. Thus, synthetic ATP-competitive inhibitors for hIKK-2 have been developed as anti-inflammatory compounds. We recently reported a virtual screening protocol (doi:10.1371/journal.pone.0016903) that is able to identify hIKK-2 inhibitors that are not structurally related to any known molecule that inhibits hIKK-2 and that have never been reported to have anti-inflammatory activity. In this study, a stricter version of this protocol was applied to an in-house database of 29,779 natural products annotated with their natural source. The search identified 274 molecules (isolated from 453 different natural extracts) predicted to inhibit hIKK-2. An exhaustive bibliographic search revealed that anti-inflammatory activity has been previously described for: (a) 36 out of these 453 extracts; and (b) 17 out of 30 virtual screening hits present in these 36 extracts. Only one of the remaining 13 hit molecules in these extracts shows chemical similarity with known synthetic hIKK-2 inhibitors. Therefore, it is plausible that a significant portion of the remaining 12 hit molecules are lead-hopping candidates for the development of new hIKK-2 inhibitors.

• The lipid-lowering effect of dietary proanthocyanidins in rats involves both chylomicron-rich and VLDL-rich fractions.

  Authors: Helena Quesada, Sabina Díaz, David Pajuelo, Anabel Fernández-Iglesias, Santiago Garcia-Vallvé, Gerard Pujadas, M Josepa Salvadó, Lluis Arola, Cinta Bladé

  The British journal of nutrition. 10/2011;

  Proanthocyanidins have been shown to improve postprandial hypertriacylglycerolaemia. The present study aims to determine the actual contribution of chylomicrons (CM) and VLDL in theProanthocyanidins have been shown to improve postprandial hypertriacylglycerolaemia. The present study aims to determine the actual contribution of chylomicrons (CM) and VLDL in the hypotriacylglycerolaemic action of grape seed proanthocyanidin extract (GSPE) in the postprandial state and to characterise the mechanisms by which the GSPE treatment reduces TAG-rich lipoproteins in vivo. A plasma lipid tolerance test was performed on rats fasted for 14 h and orally loaded with lard containing either GSPE or not. GSPE (250 mg/kg body weight) markedly blocked the increase in plasma TAG induced by lard, with a statistically significant reduction of 22 % in the area under the curve. The VLDL-rich fraction was the major contributor (72 %) after 1 h, whereas the CM-rich fraction was the major contributor (85 %) after 3 h. At 5 and 7 h after treatment, CM-rich and VLDL-rich fractions showed a similar influence. Plasma post-heparin lipoprotein lipase (LPL) activity and LPL mRNA levels in white adipose tissue and muscle were not affected by GSPE. On the contrary, GSPE treatment significantly repressed (30 %) the secretion of VLDL-TAG. In the liver, GSPE treatment induced different effects on the expression of acyl-coenzyme A synthetase long-chain family member 1, Apoc3 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase at 1 h and Cd36 at 5 h, compared to those induced by lard. Furthermore, GSPE treatment significantly increased the activity of carnitine palmitoyltransferase 1a at 1 h. In conclusion, both CM-rich and VLDL-rich fractions contributed to the hypotriacylglycerolaemic action of GSPE, but their influence depended on time. GSPE induces hypotriacylglycerolaemic actions by repressing lipoprotein secretion and not by increasing LPL activity.

• Structural insights for the design of new PPARgamma partial agonists with high binding affinity and low transactivation activity.

  Authors: Laura Guasch, Esther Sala, Cristina Valls, Mayte Blay, Miquel Mulero, Lluís Arola, Gerard Pujadas, Santiago Garcia-Vallvé

  Journal of computer-aided molecular design. 06/2011; 25(8):717-28.

  Peroxisome Proliferator-Activated Receptor γ (PPARγ) full agonists are molecules with powerful insulin-sensitizing action that are used as antidiabetic drugs. Unfortunately, these compounds alsoPeroxisome Proliferator-Activated Receptor γ (PPARγ) full agonists are molecules with powerful insulin-sensitizing action that are used as antidiabetic drugs. Unfortunately, these compounds also present various side effects. Recent results suggest that effective PPARγ agonists should show a low transactivation activity but a high binding affinity to inhibit phosphorylation at Ser273. We use several structure activity relationship studies of synthetic PPARγ agonists to explore the different binding features of full and partial PPARγ agonists with the aim of differentiating the features needed for binding and those needed for the transactivation activity of PPARγ. Our results suggest that effective partial agonists should have a hydrophobic moiety and an acceptor site with an appropriate conformation to interact with arm II and establish a hydrogen bond with Ser342 or an equivalent residue at arm III. Despite the fact that interactions with arm I increase the binding affinity, this region should be avoided in order to not increase the transactivation activity of potential PPARγ partial agonists.

• Identification of human IKK-2 inhibitors of natural origin (part I): modeling of the IKK-2 kinase domain, virtual screening and activity assays.

  Authors: Esther Sala, Laura Guasch, Justyna Iwaszkiewicz, Miquel Mulero, Maria-Josepa Salvadó, Montserrat Pinent, Vincent Zoete, Aurélien Grosdidier, Santiago Garcia-Vallvé, Olivier Michielin, Gerard Pujadas

  PloS one. 01/2011; 6(2):e16903.

  Their large scaffold diversity and properties, such as structural complexity and drug similarity, form the basis of claims that natural products are ideal starting points for drug design andTheir large scaffold diversity and properties, such as structural complexity and drug similarity, form the basis of claims that natural products are ideal starting points for drug design and development. Consequently, there has been great interest in determining whether such molecules show biological activity toward protein targets of pharmacological relevance. One target of particular interest is hIKK-2, a serine-threonine protein kinase belonging to the IKK complex that is the primary component responsible for activating NF-κB in response to various inflammatory stimuli. Indeed, this has led to the development of synthetic ATP-competitive inhibitors for hIKK-2. Therefore, the main goals of this study were (a) to use virtual screening to identify potential hIKK-2 inhibitors of natural origin that compete with ATP and (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits. We thus predicted that 1,061 out of the 89,425 natural products present in the studied database would inhibit hIKK-2 with good ADMET properties. Notably, when these 1,061 molecules were merged with the 98 synthetic hIKK-2 inhibitors used in this study and the resulting set was classified into ten clusters according to chemical similarity, there were three clusters that contained only natural products. Five molecules from these three clusters (for which no anti-inflammatory activity has been previously described) were then selected for in vitro activity testing, in which three out of the five molecules were shown to inhibit hIKK-2. We demonstrated that our virtual-screening protocol was successful in identifying lead compounds for developing new inhibitors for hIKK-2, a target of great interest in medicinal chemistry. Additionally, all the tools developed during the current study (i.e., the homology model for the hIKK-2 kinase domain and the pharmacophore) will be made available to interested readers upon request.

• In Silico Prediction of the Origin of Replication among Bacteria: A Case Study of Bacteroides thetaiotaomicron.

  Authors: Albert Pallejà, Eduard Guzman, Santiago Garcia-Vallvé, Antoni Romeu

  Omics : a journal of integrative biology. 07/2008;

  Abstract The initiation of chromosomal replication occurs only once during the prokaryote cell cycle. Some origins of replication have been experimentally determined and have led to the developmentAbstract The initiation of chromosomal replication occurs only once during the prokaryote cell cycle. Some origins of replication have been experimentally determined and have led to the development of in silico approaches to find the origin of replication among other prokaryotes. DNA base composition asymmetry is the basis of numerous in silico methods used to detect the origin and terminus of replication in prokaryotes. However, the composition asymmetry does not allow us to locate precisely the positions of the origin and terminus. Since DNA replication is a key step in the cell cycle it is important to determine properly the origin and terminus regions. Therefore, we have reviewed here the methods, tools, and databases for predicting the origins and terminuses of replication, and we have proposed some complementary analyses to reinforce these predictions. These analyses include finding the dnaA gene and its binding sites; making BLAST analyses of the intergenic sequences compared to related species; studying the gene order around the origin sequence; and studying the distribution of the genes encoded in the leading versus the lagging strand.

• E-CAI: a novel server to estimate an expected value of Codon Adaptation Index (eCAI).

  Authors: Pere Puigbò, Ignacio G Bravo, Santiago Garcia-Vallvé

  BMC bioinformatics. 02/2008; 9:65.

  BACKGROUND: The Codon Adaptation Index (CAI) is a measure of the synonymous codon usage bias for a DNA or RNA sequence. It quantifies the similarity between the synonymous codon usage of a gene andBACKGROUND: The Codon Adaptation Index (CAI) is a measure of the synonymous codon usage bias for a DNA or RNA sequence. It quantifies the similarity between the synonymous codon usage of a gene and the synonymous codon frequency of a reference set. Extreme values in the nucleotide or in the amino acid composition have a large impact on differential preference for synonymous codons. It is thence essential to define the limits for the expected value of CAI on the basis of sequence composition in order to properly interpret the CAI and provide statistical support to CAI analyses. Though several freely available programs calculate the CAI for a given DNA sequence, none of them corrects for compositional biases or provides confidence intervals for CAI values. RESULTS: The E-CAI server, available at http://genomes.urv.es/CAIcal/E-CAI, is a web-application that calculates an expected value of CAI for a set of query sequences by generating random sequences with G+C and amino acid content similar to those of the input. An executable file, a tutorial, a Frequently Asked Questions (FAQ) section and several examples are also available. To exemplify the use of the E-CAI server, we have analysed the codon adaptation of human mitochondrial genes that codify a subunit of the mitochondrial respiratory chain (excluding those genes that lack a prokaryotic orthologue) and are encoded in the nuclear genome. It is assumed that these genes were transferred from the proto-mitochondrial to the nuclear genome and that its codon usage was then ameliorated. CONCLUSION: The E-CAI server provides a direct threshold value for discerning whether the differences in CAI are statistically significant or whether they are merely artifacts that arise from internal biases in the G+C composition and/or amino acid composition of the query sequences.

• HEG-DB: a database of predicted highly expressed genes in prokaryotic complete genomes under translational selection.

  Authors: Pere Puigbò, Antoni Romeu, Santiago Garcia-Vallvé

  Nucleic acids research. 02/2008; 36(Database issue):D524-7.

  The highly expressed genes database (HEG-DB) is a genomic database that includes the prediction of which genes are highly expressed in prokaryotic complete genomes under strong translationalThe highly expressed genes database (HEG-DB) is a genomic database that includes the prediction of which genes are highly expressed in prokaryotic complete genomes under strong translational selection. The current version of the database contains general features for almost 200 genomes under translational selection, including the correspondence analysis of the relative synonymous codon usage for all genes, and the analysis of their highly expressed genes. For each genome, the database contains functional and positional information about the predicted group of highly expressed genes. This information can also be accessed using a search engine. Among other statistical parameters, the database also provides the Codon Adaptation Index (CAI) for all of the genes using the codon usage of the highly expressed genes as a reference set. The 'Pathway Tools Omics Viewer' from the BioCyc database enables the metabolic capabilities of each genome to be explored, particularly those related to the group of highly expressed genes. The HEG-DB is freely available at http://genomes.urv.cat/HEG-DB.

• E-CAI: a novel server to estimate an expected value of Codon Adaptation Index (eCAI)

  Authors: Pere Puigbò, Ignacio Bravo, Santiago Garcia-Vallvé

  BMC Bioinformatics. 01/2008;

  Abstract Background The Codon Adaptation Index (CAI) is a measure of the synonymous codon usage bias for a DNA or RNA sequence. It quantifies the similarity between the synonymous codon usage of aAbstract Background The Codon Adaptation Index (CAI) is a measure of the synonymous codon usage bias for a DNA or RNA sequence. It quantifies the similarity between the synonymous codon usage of a gene and the synonymous codon frequency of a reference set. Extreme values in the nucleotide or in the amino acid composition have a large impact on differential preference for synonymous codons. It is thence essential to define the limits for the expected value of CAI on the basis of sequence composition in order to properly interpret the CAI and provide statistical support to CAI analyses. Though several freely available programs calculate the CAI for a given DNA sequence, none of them corrects for compositional biases or provides confidence intervals for CAI values. Results The E-CAI server, available at http://genomes.urv.es/CAIcal/E-CAI , is a web-application that calculates an expected value of CAI for a set of query sequences by generating random sequences with G+C and amino acid content similar to those of the input. An executable file, a tutorial, a Frequently Asked Questions (FAQ) section and several examples are also available. To exemplify the use of the E-CAI server, we have analysed the codon adaptation of human mitochondrial genes that codify a subunit of the mitochondrial respiratory chain (excluding those genes that lack a prokaryotic orthologue) and are encoded in the nuclear genome. It is assumed that these genes were transferred from the proto-mitochondrial to the nuclear genome and that its codon usage was then ameliorated. Conclusion The E-CAI server provides a direct threshold value for discerning whether the differences in CAI are statistically significant or whether they are merely artifacts that arise from internal biases in the G+C composition and/or amino acid composition of the query sequences.

• OPTIMIZER: a web server for optimizing the codon usage of DNA sequences.

  Authors: Pere Puigbò, Eduard Guzmán, Antoni Romeu, Santiago Garcia-Vallvé

  Nucleic acids research. 08/2007; 35(Web Server issue):W126-31.

  OPTIMIZER is an on-line application that optimizes the codon usage of a gene to increase its expression level. Three methods of optimization are available: the 'one amino acid-one codon' method, aOPTIMIZER is an on-line application that optimizes the codon usage of a gene to increase its expression level. Three methods of optimization are available: the 'one amino acid-one codon' method, a guided random method based on a Monte Carlo algorithm, and a new method designed to maximize the optimization with the fewest changes in the query sequence. One of the main features of OPTIMIZER is that it makes it possible to optimize a DNA sequence using pre-computed codon usage tables from a predicted group of highly expressed genes from more than 150 prokaryotic species under strong translational selection. These groups of highly expressed genes have been predicted using a new iterative algorithm. In addition, users can use, as a reference set, a pre-computed table containing the mean codon usage of ribosomal protein genes and, as a novelty, the tRNA gene-copy numbers. OPTIMIZER is accessible free of charge at http://genomes.urv.es/OPTIMIZER.

• TOPD/FMTS: a new software to compare phylogenetic trees.

  Authors: Pere Puigbò, Santiago Garcia-Vallvé, James O McInerney

  Bioinformatics (Oxford, England). 07/2007; 23(12):1556-8.

  SUMMARY: TOPD/FMTS has been developed to evaluate similarities and differences between phylogenetic trees. The software implements several new algorithms (including the Disagree method that returnsSUMMARY: TOPD/FMTS has been developed to evaluate similarities and differences between phylogenetic trees. The software implements several new algorithms (including the Disagree method that returns the taxa, that disagree between two trees and the Nodal method that compares two trees using nodal information) and several previously described methods (such as the Partition method, Triplets or Quartets) to compare phylogenetic trees. One of the novelties of this software is that the FMTS (From Multiple to Single) program allows the comparison of trees that contain both orthologs and paralogs. Each option is also complemented with a randomization analysis to test the null hypothesis that the similarity between two trees is not better than chance expectation. AVAILABILITY: The Perl source code of TOPD/FMTS is available at http://genomes.urv.es/topd.

• Frameshift mutation events in beta-glucosidases.

  Authors: Antonio Rojas, Santiago Garcia-Vallvé, Miguel A Montero, Lluís Arola, Antoni Romeu

  Gene. 10/2003; 314:191-9.

  Compensated frameshift mutation is a modification of the reading frame of a gene that takes place by way of various molecular events. It appears to be a widespread event that is only observed whenCompensated frameshift mutation is a modification of the reading frame of a gene that takes place by way of various molecular events. It appears to be a widespread event that is only observed when homologous amino acid and nucleodotide sequences are compared. To identify these mutation events, the sequence analysis rationale was based on the search for short regions that would have much lower degrees of conservation in protein, but not in DNA, in well-conserved beta-glucosidase families. We have restricted our study to a seed set of sequences of O-glycoside hydrolase families 1 and 3. We found compensated frameshift mutation in the family of 1 beta-glucosidases for the Erwinia herbicola, Cellulomonas fimi, and (non-cyanogenic) Trifolium repens gene sequences, and in the family of 3 beta-glucosidases for the Clostridium thermocellum and Clostridium stercorarium gene sequences. By computational treatment, the observed mutation events in the gene frameshifting sub-sequence have been neutralised. Each nucleotide insertion must be eliminated and each nucleotide deletion must be substituted by the symbol N (any nucleotide). When the frameshifting fragments of the amino acid sequences were substituted by the computationally neutralised subsequences, the beta-glucosidase alignments were improved. We also discuss the structural implications of the compensated frameshift mutations events.

• Simultaneous horizontal gene transfer of a gene coding for ribosomal protein l27 and operational genes in Arthrobacter sp.

  Authors: Santiago Garcia-Vallvé, Francesc X Simó, Miguel A Montero, Lluís Arola, Antoni Romeu

  Journal of molecular evolution. 01/2003; 55(6):632-7.

  Phylogenetic analysis of bacterial L27 ribosomal proteins showed that, against taxonomy, the L27 protein from the Actinobacteria Arthrobacter sp. clusters with protein sequences from the BacillusPhylogenetic analysis of bacterial L27 ribosomal proteins showed that, against taxonomy, the L27 protein from the Actinobacteria Arthrobacter sp. clusters with protein sequences from the Bacillus group. The L27 gene clusters in the Arthrobacter sp. genome with six genes responsible for creatinine and sarcosine degradation. Phylogenetic analyses of orthologue proteins encoded by three of these genes also showed a phylogenetic relationship with Bacillus species. Comparisons between the synonymous codon usage of the Arthrobacter sp. genes and those from complete genomes showed that Arthrobacter genes encoding the L27 ribosomal protein and the proteins responsible for the degradation of creatinine and sarcosine have a codon usage that is more similar to that of Bacillus species than that of Arthrobacter. We suggest that the Arthrobacter sp. genes encoding the L27 ribosomal protein and the proteins responsible for the degradation of creatinine and sarcosine were acquired simultaneously through horizontal gene transfer from an unknown Bacillus species.

• HGT-DB: a database of putative horizontally transferred genes in prokaryotic complete genomes.

  Authors: Santiago Garcia-Vallvé, Eduard Guzmán, M. A. Montero, Antoni Romeu

  Nucleic Acids Research. 01/2003; 31:187-189.

• Genetic variation between Helicobacter pylori strains: gene acquisition or loss?

  Authors: Santiago Garcia-Vallvé, Paul J. Janssen, Christos A Ouzounis

  Trends in microbiology. 11/2002; 10(10):445-7.

  Previously identified strain-specific genes of Helicobacter pylori were analysed for GC content and preference in codon usage. The results indicate that in H. pylori strain specificity is mainlyPreviously identified strain-specific genes of Helicobacter pylori were analysed for GC content and preference in codon usage. The results indicate that in H. pylori strain specificity is mainly driven by gene uptake. Incoming strains of Helicobacter or other species can occasionally donate genes but the identification of the donor species is hampered by ongoing evolutionary processes and the lack of an adequate number, or indeed a total absence, of gene homologues.