Reducing the Flexibility of Type II Dehydroquinase for Inhibition: A Fragment‐Based Approach and Molecular Dynamics Study

This is the peer-reviewed version of the following article: Peón, A., Robles, A., Blanco, B., Convertino, M., Thompson, P., & Hawkins, A. et al. (2017). Reducing the Flexibility of Type II Dehydroquinase for Inhibition: A Fragment-Based Approach and Molecular Dynamics Study. Chemmedchem, 12(18), 1512-1524, which has been published in final form at https://doi.org/10.1002/cmdc.201700396. This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-ArchivingA multidisciplinary approach was used to identify and optimize a quinazolinedione‐based ligand that would decrease the flexibility of the substrate‐covering loop (catalytic loop) of the type II dehydroquinase from Helicobacter pylori. This enzyme, which is essential for the survival of this bacterium, is involved in the biosynthesis of aromatic amino acids. A computer‐aided fragment‐based protocol (ALTA) was first used to identify the aromatic fragments able to block the interface pocket that separates two neighboring enzyme subunits and is located at the active site entrance. Chemical modification of its non‐aromatic moiety through an olefin cross‐metathesis and Seebach's self‐reproduction of chirality synthetic principle allowed the development of a quinazolinedione derivative that disables the catalytic loop plasticity, which is essential for the enzyme′s catalytic cycle. Molecular dynamics simulations revealed that the ligand would force the catalytic loop into an inappropriate arrangement for catalysis by strong interactions with the catalytic tyrosine and by expelling the essential arginine out of the active siteSecretaría de Estado de Investigación, Desarrollo e Innovación. Grant Numbers: SAF2013-42899-R, SAF2016-75638-R Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia. Grant Number: ED431G/09 European Regional Development Fund Ministerio de Educación, Cultura y DeporteS

Search for single top quarks in the tau+jets channel using 4.8 fb−1^{-1} of ppˉp\bar{p} collision data

We present the first direct search for single top quark production using tau leptons. The search is based on 4.8 fb$^{-1}$ of integrated luminosity collected in $p\bar{p}$ collisions at $\sqrt{s}$=1.96 TeV with the D0 detector at the Fermilab Tevatron Collider. We select events with a final state including an isolated tau lepton, missing transverse energy, two or three jets, one or two of them $b$ tagged. We use a multivariate technique to discriminate signal from background. The number of events observed in data in this final state is consistent with the signal plus background expectation. We set in the tau+jets channel an upper limit on the single top quark cross section of \TauLimObs pb at the 95% C.L. This measurement allows a gain of 4% in expected sensitivity for the observation of single top production when combining it with electron+jets and muon+jets channels already published by the D0 collaboration with 2.3 fb$^{-1}$ of data. We measure a combined cross section of \SuperCombineXSall pb, which is the most precise measurement to date.Comment: 12 pages, 5 figure

b-Jet Identification in the D0 Experiment

Algorithms distinguishing jets originating from b quarks from other jet flavors are important tools in the physics program of the D0 experiment at the Fermilab Tevatron p-pbar collider. This article describes the methods that have been used to identify b-quark jets, exploiting in particular the long lifetimes of b-flavored hadrons, and the calibration of the performance of these algorithms based on collider data.Comment: submitted to Nuclear Instruments and Methods in Physics Research

Search for Large extra spatial dimensions in the dielectron and diphoton channels in ppˉ\bm{p\bar{p}} collisions at s=\bm{\sqrt{s}=}1.96 TeV

We report on a search for large extra spatial dimensions in the dielectron and diphoton channels using a data sample of 1.05 \invfb of \ppb collisions at a center-of-mass energy of 1.96 TeV collected by the D0 detector at the Fermilab Tevatron Collider. The invariant mass spectrum of the data agrees well with the prediction of the standard model. We find 95% C.L. lower limits on the effective Planck scale between 2.1 and 1.3 TeV for 2 to 7 extra dimensions.Comment: 7 pages, 3 figures, 3 tables, submitted to Phys. Rev. Let

Search for resonant diphoton production with the D0 detector

We present a search for a narrow resonance in the inclusive diphoton final state using 2.7 fb-1 of data collected with the D0 detector at the Fermilab Tevatron ppbar Collider. We observe good agreement between the data and the background prediction, and set the first 95% C.L. upper limits on the production cross section times the branching ratio for decay into a pair of photons for resonance masses between 100 and 150 GeV. This search is also interpreted in the context of several models of electroweak symmetry breaking with a Higgs boson decaying into two photons.Comment: 7 pages, 3 figures

Search for charged massive long-lived particles with the D0 detector

We search for charged massive long-lived particles using 1.1 fb$^{-1}$ of data collected by the D0 detector at the Fermilab Tevatron $p\bar{p}$ Collider. Time-of-flight information is used to search for pair produced long-lived tau sleptons, gaugino-like charginos, and higgsino-like charginos. We find no evidence of a signal and set 95% C.L. cross section upper limits for staus, which vary from 0.31pb to 0.04pb for stau masses between 60 GeV and 300 GeV. We also set lower mass limits of 206 GeV (171 GeV) for pair produced charged gauginos (higgsinos).Comment: To be submitted to Phys. Rev. Letters, V2: updated the figures and references, V3: final version submitted to PRL and changes in title and abstracts from "stable" to "long-lived

Measurement of Z/gamma*+jet+X angular distributions in ppbar collisions at sqrt{s}=1.96 TeV

We present the first measurements at a hadron collider of differential cross sections for Z+jet+X production in delta phi(Z, jet), |delta y(Z, jet)| and |y_boost(Z, jet)|. Vector boson production in association with jets is an excellent probe of QCD and constitutes the main background to many small cross section processes, such as associated Higgs production. These measurements are crucial tests of the predictions of perturbative QCD and current event generators, which have varied success in describing the data. Using these measurements as inputs in tuning event generators will increase the experimental sensitivity to rare signals.Comment: Published in Physics Letters B 682 (2010), pp. 370-380. 15 pages, 6 figure

Measurement of the p-pbar -> Wgamma + X cross section at sqrt(s) = 1.96 TeV and WWgamma anomalous coupling limits

The WWgamma triple gauge boson coupling parameters are studied using p-pbar -> l nu gamma + X (l = e,mu) events at sqrt(s) = 1.96 TeV. The data were collected with the DO detector from an integrated luminosity of 162 pb^{-1} delivered by the Fermilab Tevatron Collider. The cross section times branching fraction for p-pbar -> W(gamma) + X -> l nu gamma + X with E_T^{gamma} > 8 GeV and Delta R_{l gamma} > 0.7 is 14.8 +/- 1.6 (stat) +/- 1.0 (syst) +/- 1.0 (lum) pb. The one-dimensional 95% confidence level limits on anomalous couplings are -0.88 < Delta kappa_{gamma} < 0.96 and -0.20 < lambda_{gamma} < 0.20.Comment: Submitted to Phys. Rev. D Rapid Communication

Measurement of the ttbar Production Cross Section in ppbar Collisions at sqrt{s} = 1.96 TeV using Kinematic Characteristics of Lepton + Jets Events

We present a measurement of the top quark pair ttbar production cross section in ppbar collisions at a center-of-mass energy of 1.96 TeV using 230 pb**{-1} of data collected by the DO detector at the Fermilab Tevatron Collider. We select events with one charged lepton (electron or muon), large missing transverse energy, and at least four jets, and extract the ttbar content of the sample based on the kinematic characteristics of the events. For a top quark mass of 175 GeV, we measure sigma(ttbar) = 6.7 {+1.4-1.3} (stat) {+1.6- 1.1} (syst) +/-0.4 (lumi) pb, in good agreement with the standard model prediction.Comment: submitted to Phys.Rev.Let