MOTIVATION: The in silico prediction of potential interactions between drugs and target proteins is of core importance for the identification of new drugs or novel targets for existing drugs. ...However, only a tiny portion of all drug–target pairs in current datasets are experimentally validated interactions. This motivates the need for developing computational methods that predict true interaction pairs with high accuracy. RESULTS: We show that a simple machine learning method that uses the drug–target network as the only source of information is capable of predicting true interaction pairs with high accuracy. Specifically, we introduce interaction profiles of drugs (and of targets) in a network, which are binary vectors specifying the presence or absence of interaction with every target (drug) in that network. We define a kernel on these profiles, called the Gaussian Interaction Profile (GIP) kernel, and use a simple classifier, (kernel) Regularized Least Squares (RLS), for prediction drug–target interactions. We test comparatively the effectiveness of RLS with the GIP kernel on four drug–target interaction networks used in previous studies. The proposed algorithm achieves area under the precision–recall curve (AUPR) up to 92.7, significantly improving over results of state-of-the-art methods. Moreover, we show that using also kernels based on chemical and genomic information further increases accuracy, with a neat improvement on small datasets. These results substantiate the relevance of the network topology (in the form of interaction profiles) as source of information for predicting drug–target interactions. AVAILABILITY: Software and Supplementary Material are available at http://cs.ru.nl/~tvanlaarhoven/drugtarget2011/. CONTACT: tvanlaarhoven@cs.ru.nl; elenam@cs.ru.nl Supplementary Information: Supplementary data are available at Bioinformatics online.
We describe duplicate leptin genes in zebrafish (Danio rerio) that share merely 24% amino acid identity with each other and only 18% with human leptin. We were also able to retrieve a second leptin ...gene in medaka (Oryzias latipes). The presence of duplicate leptin genes in these two distantly related teleosts suggests that duplicate leptin genes are a common feature of teleostean fishes. Despite low primary sequence conservation, we are confident in assigning orthology between mammalian and zebrafish leptins for several reasons. First, both zebrafish leptins share their characteristic gene structure and display key features of conserved synteny with mammalian leptin genes. Secondly, the cysteine residues that make up leptin's single disulphide bridge are equally spaced in mammalian and zebrafish leptins and are unique among all members of the class-I helical cytokine family. Thirdly, the zebrafish leptins cluster with other fish leptins and mammalian leptins in phylogenetic analysis, supported by high bootstrap values. Within the leptin cluster, leptin-b forms a separate clade with the leptin-b orthologue from medaka. Finally, our prediction of the tertiary structures shows that both leptins conform to the typical four alpha-helix bundle structure of the class-I alpha-helical cytokines. The zebrafish leptins are differentially expressed; the liver shows high leptin-a expression (in concordance with what we observed for carp leptins), while leptin-b is expressed at much lower levels, which are downregulated further upon fasting. The finding of duplicate leptin genes in teleosts adds to our understanding of the evolution of leptin physiology in the early vertebrate lineage.
A Flexible Approach to Induced Fit Docking Nabuurs, Sander B; Wagener, Markus; de Vlieg, Jacob
Journal of medicinal chemistry,
12/2007, Letnik:
50, Številka:
26
Journal Article
Recenzirano
We present Fleksy, a new approach to consider both ligand and receptor flexibility in small molecule docking. Pivotal to our method is the use of a receptor ensemble to describe protein flexibility. ...To construct these ensembles, we use a backbone-dependent rotamer library and implement the concept of interaction sampling. The latter allows the evaluation of different orientations of ambivalent interaction partners. The docking stage consists of an ensemble-based soft-docking experiment using FlexX-Ensemble, followed by an effective flexible receptor–ligand complex optimization using Yasara. Fleksy produces a set of receptor–ligand complexes ranked using a consensus scoring function combining docking scores and force field energies. Averaged over three cross-docking datasets, containing 35 different receptor–ligand complexes in total, Fleksy reproduces the observed binding mode within 2.0 Å for 78% of the complexes. This compares favorably to the rigid receptor FlexX program, which on average reaches a success rate of 44% for these datasets.
Translation termination is accomplished by proteins of the Class I release factor family (RF) that recognize stop codons and catalyze the ribosomal release of the newly synthesized peptide. Bacteria ...have two canonical RFs: RF1 recognizes UAA and UAG, RF2 recognizes UAA and UGA. Despite that these two release factor proteins are sufficient for de facto translation termination, the eukaryotic organellar RF protein family, which has evolved from bacterial release factors, has expanded considerably, comprising multiple subfamilies, most of which have not been functionally characterized or formally classified. Here, we integrate multiple sources of information to analyze the remarkable differentiation of the RF family among organelles. We document the origin, phylogenetic distribution and sequence structure features of the mitochondrial and plastidial release factors: mtRF1a, mtRF1, mtRF2a, mtRF2b, mtRF2c, ICT1, C12orf65, pRF1, and pRF2, and review published relevant experimental data. The canonical release factors (mtRF1a, mtRF2a, pRF1, and pRF2) and ICT1 are derived from bacterial ancestors, whereas the others have resulted from gene duplications of another release factor. These new RF family members have all lost one or more specific motifs relevant for bona fide release factor function but are mostly targeted to the same organelle as their ancestor. We also characterize the subset of canonical release factor proteins that bear nonclassical PxT/SPF tripeptide motifs and provide a molecular-model-based rationale for their retained ability to recognize stop codons. Finally, we analyze the coevolution of canonical RFs with the organellar genetic code. Although the RF presence in an organelle and its stop codon usage tend to coevolve, we find three taxa that encode an RF2 without using UGA stop codons, and one reverse scenario, where mamiellales green algae use UGA stop codons in their mitochondria without having a mitochondrial type RF2. For the latter, we put forward a "stop-codon reinvention" hypothesis that involves the retargeting of the plastid release factor to the mitochondrion.
Phosphoribosylpyrophosphate synthetases (PRSs) catalyze the first step of nucleotide synthesis. Nucleotides are central to cell function, being the building blocks of nucleic acids and serving as ...cofactors in cellular signaling and metabolism. With this in mind, it is remarkable that mutations in
phosphoribosylpyrophosphate synthetase 1 (
PRPS1), which is the most ubiquitously expressed gene of the three PRS genes, are compatible with life. Mutations described thus far in
PRPS1 are all missense mutations that result in PRS-I superactivity or in variable levels of decreased activity, resulting in X-linked Charcot-Marie-Tooth disease-5 (CMTX5), Arts syndrome, and X-linked nonsyndromic sensorineural deafness (DFN2). Patients with PRS-I superactivity primarily present with uric acid overproduction, mental retardation, ataxia, hypotonia, and hearing impairment. Postlingual progressive hearing loss is found as an isolated feature in DFN2 patients. Patients with CMTX5 and Arts syndrome have peripheral neuropathy, including hearing impairment and optic atrophy. However, patients with Arts syndrome are more severely affected because they also have central neuropathy and an impaired immune system. The neurological phenotype in all four
PRPS1-related disorders seems to result primarily from reduced levels of GTP and possibly other purine nucleotides including ATP, suggesting that these disorders belong to the same disease spectrum. Preliminary results of
S-adenosylmethionine (SAM) supplementation in two Arts syndrome patients show improvement of their condition, indicating that SAM supplementation in the diet could alleviate some of the symptoms of patients with
PRPS1 spectrum diseases by replenishing purine nucleotides (J.C., unpublished data).
Discovery of Small Molecule CD40–TRAF6 Inhibitors Zarzycka, Barbara; Seijkens, Tom; Nabuurs, Sander B ...
Journal of chemical information and modeling,
02/2015, Letnik:
55, Številka:
2
Journal Article
Recenzirano
The CD154–CD40 receptor complex plays a pivotal role in several inflammatory pathways. Attempts to inhibit the formation of this complex have resulted in systemic side effects. Downstream inhibition ...of the CD40 signaling pathway therefore seems a better way to ameliorate inflammatory disease. To relay a signal, the CD40 receptor recruits adapter proteins called tumor necrosis factor receptor-associated factors (TRAFs). CD40–TRAF6 interactions are known to play an essential role in several inflammatory diseases. We used in silico, in vitro, and in vivo experiments to identify and characterize compounds that block CD40–TRAF6 interactions. We present in detail our drug docking and optimization pipeline and show how we used it to find lead compounds that reduce inflammation in models of peritonitis and sepsis. These compounds appear to be good leads for drug development, given the observed absence of side effects and their demonstrated efficacy for peritonitis and sepsis in mouse models.
Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants. Here, we report the identification of a rare, highly penetrant missense mutation in CFI ...encoding a p.Gly119Arg substitution that confers high risk of AMD (P = 3.79 × 10⁻⁶; odds ratio (OR) = 22.20, 95% confidence interval (CI) = 2.98-164.49). Plasma and sera from cases carrying the p.Gly119Arg substitution mediated the degradation of C3b, both in the fluid phase and on the cell surface, to a lesser extent than those from controls. Recombinant protein studies showed that the Gly119Arg mutant protein is both expressed and secreted at lower levels than wild-type protein. Consistent with these findings, human CFI mRNA encoding Arg119 had reduced activity compared to wild-type mRNA encoding Gly119 in regulating vessel thickness and branching in the zebrafish retina. Taken together, these findings demonstrate that rare, highly penetrant mutations contribute to the genetic burden of AMD.
The stress hormone cortisol is deeply involved in immune regulation in all vertebrates. Common carp (
Cyprinus carpio L.) express four corticoid receptors that may modulate immune responses: three ...glucocorticoid receptors (GR); GR1, with two splice variants (GR1a and GR1b), GR2 and a single mineralocorticoid receptor (MR). All receptors are expressed as of 4 days post-fertilization and may thus play a critical role in development and functioning of the adult immune system. Immune tissues and cells predominantly express mRNA for GRs compared to mRNA for the MR. Three-dimensional protein structure modeling predicts, and transfection assays confirm that alternative splicing of GR1 does not influence the capacity to induce transcription of effector genes. When tested for cortisol activation, GR2 is the most sensitive corticoid receptor in carp, followed by the MR and GR1a and GR1b. Lipopolysacharide (LPS) treatment of head kidney phagocytes quickly induces GR1 expression and inhibits GR2 expression. Cortisol treatment
in vivo enhances GR1a and MR mRNA expression, but only mildly, and cortisol treatment
in vitro does not affect receptor expression of phagocytes. Cortisol has no direct effect on the LPS-induced receptor profile. Therefore, an immune rather than a stress stimulus regulates GR expression. Cortisol administered at stress levels to phagocytes
in vitro significantly inhibits LPS-induced expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-12 (IL-12) (subunit p35) and of inducible nitric oxide synthase (
iNOS) expression. A physiologically differential function for GR1 and GR2 in the immune response of fish to infection is indicated.
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