Santiago Garcia-Vallvé

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

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, 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.

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

The Horizontal Gene Transfer DataBase (HGT-DB) is a genomic database that includes statistical parameters such as G+C content, codon and amino-acid usage, as well as information about which genes deviate in these parameters for prokaryotic complete genomes. Under the hypothesis that genes from distantly related species have different nucleotide compositions, these deviated genes may have been acquired by horizontal gene transfer. The current version of the database contains 88 bacterial and archaeal complete genomes, including multiple chromosomes and strains. For each genome, the database provides statistical parameters for all the genes, as well as averages and standard deviations of G+C content, codon usage, relative synonymous codon usage and amino-acid content. It also provides information about correspondence analyses of the codon usage, plus lists of extraneous group of genes in terms of G+C content and lists of putatively acquired genes. With this information, researchers can explore the G+C content and codon usage of a gene when they find incongruities in sequence-based phylogenetic trees. A search engine that allows searches for gene names or keywords for a specific organism is also available. HGT-DB is freely accessible at http://www.fut.es/~debb/HGT.

CAIcal: A combined set of tools to assess codon usage adaptation

BackgroundThe Codon Adaptation Index (CAI) was first developed to measure the synonymous codon usage bias for a DNA or RNA sequence. The CAI quantifies the similarity between the synonymous codon usage of a gene and the synonymous codon frequency of a reference set.ResultsWe describe here CAIcal, a web-server available at http://genomes.urv.es/CAIcal that includes a complete set of utilities related with the CAI. The server provides useful important features, such as the calculation and graphical representation of the CAI along either an individual sequence or a protein multiple sequence alignment translated to DNA. The automated calculation of CAI and its expected value is also included as one of the CAIcal tools. The software is also free to be downloaded as a standalone application for local use.ConclusionThe CAIcal server provides a complete set of tools to assess codon usage adaptation and to help in genome annotation.ReviewersThis article was reviewed by Purificación López-García, Dan Graur, Rob Knight and Shamil Sunyaev.

Inhibition of angiotensin-converting enzyme activity by flavonoids: structure-activity relationship studies.

Previous studies have demonstrated that certain flavonoids can have an inhibitory effect on angiotensin-converting enzyme (ACE) activity, which plays a key role in the regulation of arterial blood pressure. In the present study, 17 flavonoids belonging to five structural subtypes were evaluated in vitro for their ability to inhibit ACE in order to establish the structural basis of their bioactivity. The ACE inhibitory (ACEI) activity of these 17 flavonoids was determined by fluorimetric method at two concentrations (500 µM and 100 µM). Their inhibitory potencies ranged from 17 to 95% at 500 µM and from 0 to 57% at 100 µM. In both cases, the highest ACEI activity was obtained for luteolin. Following the determination of ACEI activity, the flavonoids with higher ACEI activity (i.e., ACEI >60% at 500 µM) were selected for further IC50 determination. The IC50 values for luteolin, quercetin, rutin, kaempferol, rhoifolin and apigenin K were 23, 43, 64, 178, 183 and 196 µM, respectively. Our results suggest that flavonoids are an excellent source of functional antihypertensive products. Furthermore, our structure-activity relationship studies show that the combination of sub-structures on the flavonoid skeleton that increase ACEI activity is made up of the following elements: (a) the catechol group in the B-ring, (b) the double bond between C2 and C3 at the C-ring, and (c) the cetone group in C4 at the C-ring. Protein-ligand docking studies are used to understand the molecular basis for these results.

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

BackgroundThe 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.ResultsThe 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.ConclusionThe 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.

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

UNLABELLED 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 Directory of Useful Decoys 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 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 Table S1. DecoyFinder is freely available at http://URVnutrigenomica-CTNS.github.com/DecoyFinder.

Molecular fingerprint similarity search in virtual screening

Molecular fingerprints have been used for a long time now in drug discovery and virtual screening. Their ease of use (requiring little to no configuration) and the speed at which substructure and similarity searches can be performed with them - paired with a virtual screening performance similar to other more complex methods - is the reason for their popularity. However, there are many types of fingerprints, each representing a different aspect of the molecule, which can greatly affect search performance. This review focuses on commonly used fingerprint algorithms, their usage in virtual screening, and the software packages and online tools that provide these algorithms.

Grape seed procyanidin extract reduces the endotoxic effects induced by lipopolysaccharide in rats

Acute inflammation is a response to injury, infection, tissue damage, or shock. Bacterial lipopolysaccharide (LPS) is an endotoxin implicated in triggering sepsis and septic shock, and LPS promotes the inflammatory response, resulting in the secretion of proinflammatory and anti-inflammatory cytokines such as the interleukins (IL-6, IL-1β, and IL-10) and tumor necrosis factor-α by the immune cells. Furthermore, nitric oxide and reactive oxygen species levels increase rapidly, which is partially due to the activation of inducible nitric oxide synthase in several tissues in response to inflammatory stimuli. Previous studies have shown that procyanidins, polyphenols present in foods such as apples, grapes, cocoa, and berries, have several beneficial properties against inflammation and oxidative stress using several in vitro and in vivo models. In this study, the anti-inflammatory and antioxidant effects of two physiological doses and two pharmaceutical doses of grape seed procyanidin extract (GSPE) were analyzed using a rat model of septic shock by the intraperitoneal injection of LPS derived from Escherichia coli. The high nutritional (75mg/kg/day) and the high pharmacological doses (200mg/kg/day) of GSPE showed anti-inflammatory effects by decreasing the proinflammatory marker NOx in the plasma, red blood cells, spleen, and liver. Moreover, the high pharmacological dose also downregulated the genes Il-6 and iNos; and the high nutritional dose decreased the glutathione ratio (GSSG/total glutathione), further illustrating the antioxidant capability of GSPE. In conclusion, several doses of GSPE can alleviate acute inflammation triggered by LPS in rats at the systemic and local levels when administered for as few as 15 days before the injection of endotoxin.

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

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 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.

Tools for in silico target fishing

Computational target fishing methods are designed to identify the most probable target of a query molecule. This process may allow the prediction of the bioactivity of a compound, the identification of the mode of action of known drugs, the detection of drug polypharmacology, drug repositioning or the prediction of the adverse effects of a compound. The large amount of information regarding the bioactivity of thousands of small molecules now allows the development of these types of methods. In recent years, we have witnessed the emergence of many methods for in silico target fishing. Most of these methods are based on the similarity principle, i.e., that similar molecules might bind to the same targets and have similar bioactivities. However, the difficult validation of target fishing methods hinders comparisons of the performance of each method. In this review, we describe the different methods developed for target prediction, the bioactivity databases most frequently used by these methods, and the publicly available programs and servers that enable non-specialist users to obtain these types of predictions. It is expected that target prediction will have a large impact on drug development and on the functional food industry.