Evidence map›Paper›PMID 25149509›Full record

ArticleBioorganic & medicinal chemistry letters2014

Combination of chiral linkers with thiophenecarboximidamide heads to improve the selectivity of inhibitors of neuronal nitric oxide synthase.

Qing Jing, Huiying Li, Linda J Roman, Pavel Martásek, Thomas L Poulos, Richard B Silverman

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Bioorganic & medicinal chemistry letters, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
0.9field-weighted citation impact, top 26% 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

4 citing papers in PubMed, 7 citations in OpenAlex.

  1. Nitric oxide synthase and structure-based inhibitor design.Nitric oxide : biology and chemistry · 2017
    Review
  2. Article
  3. Article
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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

6 authors at 4 institutions in 2 countries.

Qing JingDepartment of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA; Department of Molecular Biosciences, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA; Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA; Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
Huiying LiDepartment of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA; Department of Pharmaceutical Chemistry, University of California, Irvine, CA 92697, USA; Department of Chemistry, University of California, Irvine, CA 92697, USA.
Linda J RomanDepartment of Biochemistry, The University of Texas Health Science Center, San Antonio, TX 78384-7760, USA.
Pavel MartásekDepartment of Biochemistry, The University of Texas Health Science Center, San Antonio, TX 78384-7760, USA; Department of Pediatrics and Center for Applied Genomics, 1st School of Medicine, Charles University, Prague, Czech Republic.
Thomas L PoulosDepartment of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA; Department of Pharmaceutical Chemistry, University of California, Irvine, CA 92697, USA; Department of Chemistry, University of California, Irvine, CA 92697, USA. Electronic address: poulos@uci.edu.
Richard B SilvermanDepartment of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA; Department of Molecular Biosciences, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA; Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA; Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA. Electronic address: Agman@chem.northwestern.edu.
Northwestern University · USUniversity of California, Irvine · USCharles University · CZThe University of Texas Health Science Center at San Antonio · US

Funding

STRUCTURAL STUDIES ON NITRIC OXIDE SYNTHASER01GM057353 · NIGMS · UNIVERSITY OF CALIFORNIA-IRVINE · PI POULOS, THOMAS L · 1998 to 2018
$6.8M
Selective inhibition of nitric oxide synthase for multiple indicationsR01GM049725 · NIGMS · NORTHWESTERN UNIVERSITY · PI SILVERMAN, RICHARD B · 1994 to 2018
$6.0M
Structure/Function Modularity in Nitric Oxide SynthaseR01GM052419 · NIGMS · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI MASTERS, BETTIE SUE SILER, ROMAN, LINDA J · 1996 to 2012
$3.5M
NIGMS NIH HHS GM049725NIGMS NIH HHS GM057353NIGMS NIH HHS GM52419NIGMS NIH HHS R01 GM049725NIGMS NIH HHS R01 GM052419NIGMS NIH HHS R01 GM057353
6 · The paper itself

Abstract

To develop potent and selective nNOS inhibitors, a new series of double-headed molecules with chiral linkers that derive from natural amino acid derivatives have been designed and synthesized. The new structures integrate a thiophenecarboximidamide head with two types of chiral linkers, presenting easy synthesis and good inhibitory properties. Inhibitor (S)-9b exhibits a potency of 14.7 nM against nNOS and is 1134 and 322-fold more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 9b and propionate A on the heme and tetrahydrobiopterin (H4B) in nNOS, but not eNOS, contributes to its high selectivity. This work demonstrates the advantage of integrating known structures into structure optimization, and it should be possible to more readily develop compounds that incorporate bioavailability with these advanced features. Moreover, this integrative strategy is a general approach in new drug discovery.

Indexed as

Dose-Response Relationship, DrugEnzyme InhibitorsImidesModels, MolecularMolecular StructureNitric Oxide Synthase Type IStructure-Activity RelationshipThiophenesEnzyme InhibitorsImidesNitric Oxide Synthase Type IThiophenesHemeNitric oxide synthaseProtein crystallographySelective inhibitionTetrahydrobiopterinThiophenecarboximidamide

Identifiers

PMID25149509
PMCPMC4204799
OpenAlexW2066391419

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

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.