Improving performance of docking-based virtual screening by structural filtration

In the current study an innovative method of structural filtration of docked ligand poses is introduced and applied to improve the virtual screening results. The structural filter is defined by a protein-specific set of interactions that are a) structurally conserved in available structures of a particular protein with its bound ligands, and b) that can be viewed as playing the crucial role in protein-ligand binding. The concept was evaluated on a set of 10 diverse proteins, for which the corresponding structural filters were developed and applied to the results of virtual screening obtained with the Lead Finder software. The application of structural filtration resulted in a considerable improvement of the enrichment factor ranging from several folds to hundreds folds depending on the protein target. It appeared that the structural filtration had effectively repaired the deficiencies of the scoring functions that used to overestimate decoy binding, resulting into a considerably lower false positive rate. In addition, the structural filters were also effective in dealing with some deficiencies of the protein structure models that would lead to false negative predictions otherwise. The ability of structural filtration to recover relatively small but specifically bound molecules creates promises for the application of this technology in the fragment-based drug discovery.     

On differentiation of cod (Gadus morhua L.) groups in Baltic Sea

Russian Journal of Genetics - Using the AGP*, PGI-1*, PGI-2*, LDH*, IDH*, and PGM* allozyme markers, the differentiation of cod groups during the spawning period in Baltic Sea was evaluated. It was...     

European checkerspots (Melitaeini: Lepidoptera,Nymphalidae) are not aposematic – the point of view of great tits (Parus major)

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An Analysis of Microsatellite Polymorphism in the Population of the Arctic Rainbow Smelt Osmerus dentex from Eastern and Western Kamchatka

Russian Journal of Genetics - The genetic diversity of ten microsatellite loci is examined in samples of Arctic rainbow smelt. The expected heterozygosity estimates vary in the range of...     

Toward <Emphasis Type="Italic">Gadus</Emphasis> (Gadidae) genus taxonomy: Development of modern structure

According to the results of analysis of genetic differentiation and Bayesian hierarchical cluster analysis of polymorphism in microsatellite loci, it was demonstrated that the development of marginal groups represented by subspecies level taxa (Greenland (Gadus macrocephalus ogac) and White Sea (Gadus morhua marisalbi) cod) occurred in the Late Holocene in a similar scenario, but in different regions and from different initial forms. The development of these reproductively independent cod groups was a result of physiological adaptations to arctic conditions in coastal northern water areas that developed under global cooling in the Subboreal.     

New Data on the Biology of Kildin Cod Gadus morhua kildinensis (Gadidae) from Lake Mogilnoe (Kildin Island,the Barents Sea) Obtained by Echo Sounding and Underwater Photography

Journal of Ichthyology - The distribution of the Kildin cod Gadus morhua kildinensis in Lake Mogilnoye (Kildin Island, Barents Sea) is assessed based on the results of echo sounding and...     

Population structure and variability of Pacific herring (<Emphasis Type="Italic">Clupea pallasii</Emphasis>) in the White Sea,Barents and Kara Seas revealed by microsatellite DNA analyses

Pacific herring, Clupea pallasii, have recently colonised the northeast Atlantic and Arctic Oceans in the early Holocene. In a relatively short evolutionary time, the herring formed a community with a complex population structure. Previous genetic studies based on morphological, allozyme and mitochondrial DNA data have supported the existence of two herring subspecies from the White Sea and eastern Barents and Kara Seas (C. p. marisalbi and C. p. suworowi, respectively). However, the population structure of the White Sea herring has long been debated and remains controversial. The analyses of morphological and allozyme data have previously identified local spawning groups of herring in the White Sea, whereas mtDNA markers have not revealed any differentiation. We conducted one of the first studies of microsatellite variation for the purpose of investigating the genetic structure and relationship of Pacific herring among ten localities in the White Sea, the Barents Sea and the Kara Sea. Using classical genetic variance-based methods (hierarchical AMOVA, overall and pairwise F _ST comparisons), as well as the Bayesian clustering, we infer considerable genetic diversity and population structure in herring at ten microsatellite loci. Genetic differentiation was the most pronounced between the White Sea (C. p. marisalbi) versus the Barents and Kara seas (Chesha–Pechora herring, C. p. suworowi). While microsatellite variation in all C. pallasii was considerable, genetic diversity was significantly lower in C. p. suworowi, than in C. p. marisalbi. Also, tests of genetic differentiation were indicating significant differentiation within the White Sea herring between sympatric summer- and spring-spawning groups, in comparison with genetic homogeneity of the Chesha–Pechora herring.     

TSAR,a new graph–theoretical approach to computational modeling of protein side‐chain flexibility: Modeling of ionization properties of proteins

A new graph–theoretical approach called thermodynamic sampling of amino acid residues (TSAR) has been elaborated to explicitly account for the protein side chain flexibility in modeling conformation‐dependent protein properties. In TSAR, a protein is viewed as a graph whose nodes correspond to structurally independent groups and whose edges connect the interacting groups. Each node has its set of states describing conformation and ionization of the group, and each edge is assigned an array of pairwise interaction potentials between the adjacent groups. By treating the obtained graph as a belief‐network—a well‐established mathematical abstraction—the partition function of each node is found. In the current work we used TSAR to calculate partition functions of the ionized forms of protein residues. A simplified version of a semi‐empirical molecular mechanical scoring function, borrowed from our Lead Finder docking software, was used for energy calculations. The accuracy of the resulting model was validated on a set of 486 experimentally determined pK_a values of protein residues. The average correlation coefficient (R) between calculated and experimental pK_a values was 0.80, ranging from 0.95 (for Tyr) to 0.61 (for Lys). It appeared that the hydrogen bond interactions and the exhaustiveness of side chain sampling made the most significant contribution to the accuracy of pK_a calculations. Proteins 2011; © 2011 Wiley‐Liss, Inc.     

2,3-Dihydroxy-quinoxaline induces ATPase activity of Herpes Simplex Virus thymidine kinase

2,3-Dihydroxy-quinoxaline, a small molecule that promotes ATPase catalytic activity of Herpes Simplex Virus thymidine kinase (HSV-TK), was identified by virtual screening. This compound competitively inhibited HSV-TK catalyzed phosphorylation of acyclovir with K_i = 250 μM (95% CI: 106–405 μM) and dose-dependently increased the rate of the ATP hydrolysis with K_M = 112 μM (95% CI: 28–195 μM). The kinetic scheme consistent with this experimental data is proposed.     

Selective effect of the duration of the critical temperature period on some allozyme loci of Atlantic salmon Salmo salar L. (Salmonidae)

Genetic structure of juvenile fish from the populations of the Atlantic salmon Salmo salar inhabiting the rivers of Murmansk oblast, Arkhangelsk oblast, and Karelia, as well as of juveniles from hatcheries was examined at five allozymic loci: aspartate aminotransferase (AAT-4*), isocitrate dehydrogenase (IDHP-3*), iditol dehydrogenase (IDDH-2*), esterase D (ESTD*), and malic enzyme (MEP-2*). High genetic differentiation of both natural and “hatchery” juvenile fish was revealed. It was demonstrated that the gene pool of juveniles at three of the five loci tested was to a considerable degree formed by natural selection. In this case, the role of limiting factor was played by the duration of critical temperature regime in the rivers. The differentiation factors for juveniles from nature were not established, however, their clusterization pattern pointed to a possible role of natural selection in this process.