Overview of triaging the genes stored in the AEROPATH database to enable structure-based druggability predictions for <i>P</i>. <i>aeruginosa</i> proteins.

<p>Overview of triaging the genes stored in the AEROPATH database to enable structure-based druggability predictions for <i>P</i>. <i>aeruginosa</i> proteins.</p

The basis for homolog-based druggability predictions.

<p>(A) Homologous pockets whose classification correctly reflected the druggability of the parent pocket. The data was binned according to percent correct predictions among the scored pockets for each parent homolog. The number of NRDLD proteins that fitted into each category was then plotted (frequency and percentages are both shown). (B) Correct predictions in relationship to sequence identity. The percent identity between NRDLD dataset structures and homologous chains was noted. The homologs were then binned according to their percent sequence identity. The percent of homologs whose predictions matched that of the NRDLD dataset pocket was plotted for each bin. (C) Correct predictions in relationship to sequence identity of binding site residues only. Plotted as described for (B), but instead of the sequence identity only the identity of the binding site residues was used. (D) Percent correct predictions in relationship to number of assessed homologs. (E) Percent consensus in relationship to percentage of correctly predicted NRDLD dataset pockets. The NRDLD dataset pockets were binned into two categories, where either <80% or ≥80% consensus (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137279#sec010" target="_blank">methods</a>) in druggability predictions for their respective homologs was observed. The percentage of NRDLD pockets whose druggability was correctly reflected by consensus amongst their homologs was then plotted for each of these bins.</p

List of <i>P</i>. <i>aeruginosa</i> proteins predicted to possess a druggable pocket.

<p>^<b>α</b><b><i>HA</i>:</b> distinct homologous pockets assessed</p><p>^Ω<b><i>Rank</i>:</b> Chemogenomics-based druggability rank. Ranks obtained when only perturbative proteins are considered are given in brackets.</p><p>List of <i>P</i>. <i>aeruginosa</i> proteins predicted to possess a druggable pocket.</p

Accuracy, recall and precision values for training and validation sets for DrugPred 1 and 2.0.

<p>^<b>Ω</b> Values taken from Krasowski et al [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137279#pone.0137279.ref021" target="_blank">21</a>]</p><p>Accuracy, recall and precision values for training and validation sets for DrugPred 1 and 2.0.</p

Complexity of homolog-based identification of pertinent pockets in proteins.

<p>A) A hypothetical target protein is depicted with three homologous proteins. The target protein consists of two domains, one shown in blue and the other in red. These domains may be represented by complete or partial sequences in homologs. For example, homologs 1 and 2 possess short domains homologous to the target protein's blue domain. On the other hand, homolog 3 possesses a sequence match for the red domain. Each target protein domain possesses pockets (denoted by black, green, red and blue ovoids), which may or may not be identified by the presence of ligands in homologs. Here, the black pocket is also represented in homolog 3, but the green pocket is not. The red pocket is observed in both, homolog 1 and 2, but the blue pocket is only represented in homolog 1. B) Workflow to identify druggable pockets in homologs proteins.</p

Mining the ChEMBL Database: An Efficient Chemoinformatics Workflow for Assembling an Ion Channel-Focused Screening Library

The ChEMBL database was mined to efficiently assemble an ion channel-focused screening library. The compiled library consists of 3241 compounds representing 123 templates across nine ion channel categories. Compounds in the screening library are annotated with their respective ion channel category to facilitate back-tracing of prospective molecular targets from phenotypic screening results. The established workflow is adaptable to the construction of focused screening libraries for other therapeutic target classes with diverse recognition motifs

Increasing the Coverage of Medicinal Chemistry-Relevant Space in Commercial Fragments Screening

Analyzing the chemical space coverage in commercial fragment screening collections revealed the overlap between bioactive medicinal chemistry substructures and rule-of-three compliant fragments is only ∼25%. We recommend including these fragments in fragment screening libraries to maximize confidence in discovering hit matter within known bioactive chemical space, while incorporation of nonoverlapping substructures could offer novel hits in screening libraries. Using principal component analysis, polar and three-dimensional substructures display a higher-than-average enrichment of bioactive compounds, indicating increasing representation of these substructures may be beneficial in fragment screening

Locating Sweet Spots for Screening Hits and Evaluating Pan-Assay Interference Filters from the Performance Analysis of Two Lead-like Libraries

The efficiency of automated compound screening is heavily influenced by the design and the quality of the screening libraries used. We recently reported on the assembly of one diverse and one target-focused lead-like screening library. Using data from 15 enzyme-based screenings conducted using these libraries, their performance was investigated. Both libraries delivered screening hits across a range of targets, with the hits distributed across the entire chemical space represented by both libraries. On closer inspection, however, hit distribution was uneven across the chemical space, with enrichments observed in octants characterized by compounds at the higher end of the molecular weight and lipophilicity spectrum for lead-like compounds, while polar and sp³-carbon atom rich compounds were underrepresented among the screening hits. Based on these observations, we propose that screening libraries should not be evenly distributed in lead-like chemical space but be enriched in polar, aliphatic compounds. In conjunction with variable concentration screening, this could lead to more balanced hit rates across the chemical space and screening hits of higher ligand efficiency will be captured. Apart from chemical diversity, both screening libraries were shown to be clean from any pan-assay interference (PAINS) behavior. Even though some compounds were flagged to contain PAINS structural motifs, some of these motifs were demonstrated to be less problematic than previously suggested. To maximize the diversity of the chemical space sampled in a screening campaign, we therefore consider it justifiable to retain compounds containing PAINS structural motifs that were apparently clean in this analysis when assembling screening libraries

Probing the Dynamic Nature of Water Molecules and Their Influences on Ligand Binding in a Model Binding Site

The model binding site of the cytochrome <i>c</i> peroxidase (CCP) W191G mutant is used to investigate the structural and dynamic properties of the water network at the buried cavity using computational methods supported by crystallographic analysis. In particular, the differences of the hydration pattern between the uncomplexed state and various complexed forms are analyzed as well as the differences between five complexes of CCP W191G with structurally closely related ligands. The ability of docking programs to correctly handle the water molecules in these systems is studied in detail. It is found that fully automated prediction of water replacement or retention upon docking works well if some additional preselection is carried out but not necessarily if the entire water network in the cavity is used as input. On the other hand, molecular interaction fields for water calculated from static crystal structures and hydration density maps obtained from molecular dynamics simulations agree very well with crystallographically observed water positions. For one complex, the docking and MD results sensitively depend on the quality of the starting structure, and agreement is obtained only after redetermination of the crystal structure and refinement at higher resolution

Finnlines Oyj:n liikuntaluotsitoiminnan kehittäminen

Tämän opinnäytetyön tavoitteena oli kehittää Finnlines Oyj:n liikuntavastaavien eli -luotsien toimintaa ja antaa heille konkreettisia työkaluja sekä neuvoja heidän toimintaansa laivaympä-ristössä. Projektin tarkoituksena oli, että luotsit pystyvät toiminnallaan jatkossa tavoittamaan laajemmin merihenkilöstöä sekä auttamaan henkilöstöä motivoitumaan liikkumiseen laivoilla. Tässä projektissa tutkittiin ensiksi kyselyllä merihenkilöstön motiiveja liikkumiseen laivatyö-jaksoilla sekä heidän kokemuksiaan liikuntaluotsien toiminnasta tähän asti. Kyselyyn vastasi yhteensä 83 henkilöä. Tulosten pohjalta suunniteltiin liikuntaluotseille kahden päivän koulutus, johon osallistui kahdeksan henkilöä Finnlines Oyj:n henkilöstöstä. Koulutuksen tavoitteena oli ohjatun oivaltamisen ja ongelmanratkaisujen avulla ohjata luotseja kehittämään yhdessä toimintatapoja merihenkilöstön liikuntamotivaation ja liikunta-aktiivisuuden edistämiseksi. Merihenkilöstöstä 54 % oli laivatyöjaksoilla liikunnallisesti passiivisia ja he motivoituivat liik-kumaan eniten sisäisistä motivaatiotekijöistä, kuten liikunnasta saadusta hyvän olon tunteesta. Vastaajista 43 % ei ollut kuullut liikuntaluotseista ja 83 % eivät olleet ollut luotsien kanssa tekemisissä. Koulutuksen tuloksena liikuntaluotsit suunnittelivat yhdessä laivoille toteutettaviksi konkreettiset liikuntakampanjat, jotka motivoivat laajalti merihenkilöstöä liikkumaan. Lisäksi he kehittivät tapoja tuoda omaa toimintaansa enemmän esille, kuten ilmoitustauluilla luotsien esittely, ja luotsien välisen yhteydenpitokanavan. Liikuntaluotsit ovat innokkaita ja liikunta-asioista kiinnostuneita vapaaehtoisia. He ovat oivaltaneet, että heidän aktiivisuudellaan on mahdollista saada paljon aikaan. Jatkossa luotsien ja heidän yhteyshenkilöidensä välinen yhteydenpito sekä suunniteltujen toimintojen toteuttaminen ovat merkittävässä asemassa luotsien toiminnan sekä motivaation ylläpitämiseksi