Evidence map›Paper›PMID 37129190›Full record

ArticleDrug development research2023

Computational and experimental analyses of alanine racemase suggest new avenues for developing allosteric small-molecule antibiotics.

Arie van Wieren, Jacob D Durrant, Sudipta Majumdar

Open access · greenAbstract read
In one paragraph

Article in Drug development research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
0.4field-weighted citation impact, top 37% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed, 2 citations in OpenAlex.

  1. Article
  2. BioMed research international · 2024
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

3 authors at 2 institutions in 1 country.

Arie van WierenMadia Department of Chemistry, Biochemistry, Physics and Engineering, Indiana University of Pennsylvania, Indiana, Pennsylvania, USA.ORCID 0000-0003-3522-5325
Jacob D DurrantDepartment of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Sudipta MajumdarMadia Department of Chemistry, Biochemistry, Physics and Engineering, Indiana University of Pennsylvania, Indiana, Pennsylvania, USA.ORCID 0000-0002-2220-4990
Indiana University of Pennsylvania · USUniversity of Pittsburgh · US

Funding

Advancing drug-lead and chemical-probe discovery using weighted-ensemble simulations and biophysical validationR01GM132353 · NIGMS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI DURRANT, JACOB D · 2019 to 2023
$1.7M
NIGMS NIH HHS R01 GM132353NIH HHS
6 · The paper itself

Abstract

Given the ever-present threat of antibacterial resistance, there is an urgent need to identify new antibacterial drugs and targets. One such target is alanine racemase (Alr), an enzyme required for bacterial cell-wall biosynthesis. Alr is an attractive drug target because it is essential for bacterial survival but is absent in humans. Existing drugs targeting Alr lack specificity and have severe side effects. We here investigate alternative mechanisms of Alr inhibition. Alr functions exclusively as an obligate homodimer, so we probed seven conserved interactions on the dimer interface, distant from the enzymatic active site, to identify possible allosteric influences on activity. Using the Alr from Mycobacterium tuberculosis (MT) as a model, we found that the Lys261/Asp135 salt bridge is critical for catalytic activity. The Lys261Ala mutation completely inactivated the enzyme, and the Asp135Ala mutation reduced catalytic activity eight-fold. Further investigation suggested a potential drug-binding site near the Lys261/Asp135 salt bridge that may be useful for allosteric drug discovery.

Indexed as

Alanine RacemaseMycobacterium tuberculosisAnti-Bacterial AgentsCatalytic DomainDrug Resistance, BacterialHumansAlanine RacemaseAnti-Bacterial Agentsalanine racemaseantibioticcomputer-aided drug designdrug discoveryenzyme kineticsprotein structure-function

Identifiers

PMID37129190
PMCPMC10524904
OpenAlexW4367668754

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.