8
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Integration of molecular modelling and in vitro studies to inhibit LexA proteolysis

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Introduction

          As antibiotic resistance has become more prevalent, the social and economic impacts are increasingly pressing. Indeed, bacteria have developed the SOS response which facilitates the evolution of resistance under genotoxic stress. The transcriptional repressor, LexA, plays a key role in this response. Mutation of LexA to a non-cleavable form that prevents the induction of the SOS response sensitizes bacteria to antibiotics. Achieving the same inhibition of proteolysis with small molecules also increases antibiotic susceptibility and reduces drug resistance acquisition. The availability of multiple LexA crystal structures, and the unique Ser-119 and Lys-156 catalytic dyad in the protein enables the rational design of inhibitors.

          Methods

          We pursued a binary approach to inhibit proteolysis; we first investigated β-turn mimetics, and in the second approach we tested covalent warheads targeting the Ser-119 residue. We found that the cleavage site region (CSR) of the LexA protein is a classical Type II β-turn, and that published 1,2,3-triazole compounds mimic the β-turn. Generic covalent molecule libraries and a β-turn mimetic library were docked to the LexA C-terminal domain using molecular modelling methods in FlexX and CovDock respectively. The 133 highest-scoring molecules were screened for their ability to inhibit LexA cleavage under alkaline conditions. The top molecules were then tested using a RecA-mediated cleavage assay.

          Results

          The β-turn library screen did not produce any hit compounds that inhibited RecA-mediated cleavage. The covalent screen discovered an electrophilic serine warhead that can inhibit LexA proteolysis, reacting with Ser-119 via a nitrile moiety.

          Discussion

          This research presents a starting point for hit-to-lead optimisation, which could lead to inhibition of the SOS response and prevent the acquisition of antibiotic resistance.

          Related collections

          Most cited references88

          • Record: found
          • Abstract: found
          • Article: not found

          UCSF Chimera--a visualization system for exploratory research and analysis.

          The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The Protein Data Bank.

            The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide archive of structural data of biological macromolecules. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules

              To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                2235-2988
                03 March 2023
                2023
                : 13
                : 1051602
                Affiliations
                [1] 1 Cancer and Ageing Research Program, Centre for Genomics and Personalised Health, Queensland University of Technology (QUT), Translational Research Institute (TRI) , Brisbane, QLD, Australia
                [2] 2 School of Chemistry and Physics, Queensland University of Technology (QUT) , Brisbane, QLD, Australia
                [3] 3 Laboratory of Genomic Integrity, National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD, United States
                Author notes

                Edited by: Parth Sarthi Sen Gupta, Indian Institute of Science Education and Research Berhampur (IISER), India

                Reviewed by: Sunil Kumar Tripathi, Georgia State University, United States; Gopal L. Khatik, National Institute of Pharmaceutical Education and Research, India

                *Correspondence: Neha S. Gandhi, neha.gandhi@ 123456qut.edu.au ; Roger Woodgate, woodgate@ 123456mail.nih.gov

                †ORCID: John P. McDonald, orcid.org/0000-0003-2482-148X; Roger Woodgate, orcid.org/0000-0001-5581-4616; Zachariah Schuurs, orcid.org/0000-0002-5598-5252; Laura V. Croft, orcid.org/0000-0003-3875-2753; Derek J. Richard, orcid.org/0000-0002-4839-8471; Neha S. Gandhi, orcid.org/0000-0003-3119-6731

                This article was submitted to Clinical Microbiology, a section of the journal Frontiers in Cellular and Infection Microbiology

                Article
                10.3389/fcimb.2023.1051602
                10020695
                36936756
                1b4814f2-2c81-4570-b1df-8e1da61db913
                Copyright © 2023 Schuurs, McDonald, Croft, Richard, Woodgate and Gandhi

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 23 September 2022
                : 14 February 2023
                Page count
                Figures: 7, Tables: 3, Equations: 3, References: 94, Pages: 17, Words: 8021
                Funding
                This work was supported by funds from the NIH/NICHD Intramural Research Program to RW; and the Advance Queensland Industry Research Fellowship support Dr. NG and ZS.
                Categories
                Cellular and Infection Microbiology
                Original Research

                Infectious disease & Microbiology
                lexa,antibiotic resistance,covalent inhibitors,molecular docking,proteolysis

                Comments

                Comment on this article

                scite_
                0
                0
                0
                0
                Smart Citations
                0
                0
                0
                0
                Citing PublicationsSupportingMentioningContrasting
                View Citations

                See how this article has been cited at scite.ai

                scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.

                Similar content167

                Most referenced authors2,545