Literature DB >> 24900632

Fragment-based discovery of 6-azaindazoles as inhibitors of bacterial DNA ligase.

Steven Howard1, Nader Amin1, Andrew B Benowitz2, Elisabetta Chiarparin1, Haifeng Cui2, Xiaodong Deng2, Tom D Heightman1, David J Holmes2, Anna Hopkins1, Jianzhong Huang2, Qi Jin2, Constantine Kreatsoulas2, Agnes C L Martin1, Frances Massey1, Lynn McCloskey2, Paul N Mortenson1, Puja Pathuri1, Dominic Tisi1, Pamela A Williams1.   

Abstract

Herein we describe the application of fragment-based drug design to bacterial DNA ligase. X-ray crystallography was used to guide structure-based optimization of a fragment-screening hit to give novel, nanomolar, AMP-competitive inhibitors. The lead compound 13 showed antibacterial activity across a range of pathogens. Data to demonstrate mode of action was provided using a strain of S. aureus, engineered to overexpress DNA ligase.

Entities:  

Keywords:  Bacterial DNA ligase; S. aureus; fragment-based drug design; structure-based optimization

Year:  2013        PMID： 24900632      PMCID： PMC4027552          DOI： 10.1021/ml4003277

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  21 in total

1.  Ligand efficiency: a useful metric for lead selection.

Authors:  Andrew L Hopkins; Colin R Groom; Alexander Alex
Journal:  Drug Discov Today       Date:  2004-05-15       Impact factor: 7.851

2.  Novel bacterial NAD+-dependent DNA ligase inhibitors with broad-spectrum activity and antibacterial efficacy in vivo.

Authors:  Scott D Mills; Ann E Eakin; Ed T Buurman; Joseph V Newman; Ning Gao; Hoan Huynh; Kenneth D Johnson; Sushmita Lahiri; Adam B Shapiro; Grant K Walkup; Wei Yang; Suzanne S Stokes
Journal:  Antimicrob Agents Chemother       Date:  2010-12-28       Impact factor: 5.191

Review 3.  Drugs for bad bugs: confronting the challenges of antibacterial discovery.

Authors:  David J Payne; Michael N Gwynn; David J Holmes; David L Pompliano
Journal:  Nat Rev Drug Discov       Date:  2006-12-08       Impact factor: 84.694

Review 4.  DNA ligases: structure, reaction mechanism, and function.

Authors:  Alan E Tomkinson; Sangeetha Vijayakumar; John M Pascal; Tom Ellenberger
Journal:  Chem Rev       Date:  2006-02       Impact factor: 60.622

5.  Physicochemical properties of antibacterial compounds: implications for drug discovery.

Authors:  Rosemarie O'Shea; Heinz E Moser
Journal:  J Med Chem       Date:  2008-02-09       Impact factor: 7.446

6.  Assessing the lipophilicity of fragments and early hits.

Authors:  Paul N Mortenson; Christopher W Murray
Journal:  J Comput Aided Mol Des       Date:  2011-05-26       Impact factor: 3.686

Review 7.  DNA ligase: structure, mechanism, and function.

Authors:  I R Lehman
Journal:  Science       Date:  1974-11-29       Impact factor: 47.728

8.  Discovery of bacterial NAD+-dependent DNA ligase inhibitors: optimization of antibacterial activity.

Authors:  Suzanne S Stokes; Hoan Huynh; Madhusudhan Gowravaram; Robert Albert; Marta Cavero-Tomas; Brendan Chen; Jenna Harang; James T Loch; Min Lu; George B Mullen; Shannon Zhao; Ce-Feng Liu; Scott D Mills
Journal:  Bioorg Med Chem Lett       Date:  2011-06-12       Impact factor: 2.823

9.  Characterization of a temperature-sensitive DNA ligase from Escherichia coli.

Authors:  Manuel Lavesa-Curto; Heather Sayer; Desmond Bullard; Andrew MacDonald; Adam Wilkinson; Andrew Smith; Laura Bowater; Andrew Hemmings; Richard P Bowater
Journal:  Microbiology       Date:  2004-12       Impact factor: 2.777

Review 10.  DNA ligases: progress and prospects.

Authors:  Stewart Shuman
Journal:  J Biol Chem       Date:  2009-03-27       Impact factor: 5.157
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  7 in total

1.  Detection of secondary binding sites in proteins using fragment screening.

Authors:  R Frederick Ludlow; Marcel L Verdonk; Harpreet K Saini; Ian J Tickle; Harren Jhoti
Journal:  Proc Natl Acad Sci U S A       Date:  2015-12-11       Impact factor: 11.205

2.  Compound Uptake into E. coli Can Be Facilitated by N-Alkyl Guanidiniums and Pyridiniums.

Authors:  Sarah J Perlmutter; Emily J Geddes; Bryon S Drown; Stephen E Motika; Myung Ryul Lee; Paul J Hergenrother
Journal:  ACS Infect Dis       Date:  2020-11-23       Impact factor: 5.084

3.  The Search for Herbal Antibiotics: An In-Silico Investigation of Antibacterial Phytochemicals.

Authors:  Mary Snow Setzer; Javad Sharifi-Rad; William N Setzer
Journal:  Antibiotics (Basel)       Date:  2016-09-12

4.  Biochemical and Structural Characterisation of DNA Ligases from Bacteria and Archaea.

Authors:  Giulia Pergolizzi; Gerd K Wagner; Richard Peter Bowater
Journal:  Biosci Rep       Date:  2016-10-06       Impact factor: 3.840

Review 5.  The Macromolecular Machines that Duplicate the Escherichia coli Chromosome as Targets for Drug Discovery.

Authors:  Jon M Kaguni
Journal:  Antibiotics (Basel)       Date:  2018-03-14

Review 6.  Targeting DNA Replication and Repair for the Development of Novel Therapeutics against Tuberculosis.

Authors:  Michael A Reiche; Digby F Warner; Valerie Mizrahi
Journal:  Front Mol Biosci       Date:  2017-11-14

7.  Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2H-pyrazolo[4,3-c]pyridines.

Authors:  Beatričė Razmienė; Eva Řezníčková; Vaida Dambrauskienė; Radek Ostruszka; Martin Kubala; Asta Žukauskaitė; Vladimír Kryštof; Algirdas Šačkus; Eglė Arbačiauskienė
Journal:  Molecules       Date:  2021-11-08       Impact factor: 4.411
  7 in total

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