Evidence map›Paper›PMID 41759240›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2026

Discovery of a pyridine-piperazine-based small molecule that enhances the activity of peptidase neurolysin.

Heba ElSayed ElZorkany, Haya Kandil, Srinidhi Jayaraman, Asmaa Aly, Shiva Hadi Esfahani, Dhavalkumar Patel, Dennis Dannecker, Monika Maciag, Alyssa Paul, Kaitlin Lowran and 9 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of pharmacology and experimental therapeutics, 2026. 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
–field-weighted citation impact
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.

  1. Article
  2. 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

19 authors.

Heba ElSayed ElZorkanyDepartment of Foundational Medical Studies, William Beaumont School of Medicine, Oakland University, Rochester, Michigan.
Haya KandilDepartment of Foundational Medical Studies, William Beaumont School of Medicine, Oakland University, Rochester, Michigan.
Srinidhi JayaramanDepartment of Pharmaceutical Sciences and Brain Drug Discovery Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas.
Asmaa AlyDepartment of Foundational Medical Studies, William Beaumont School of Medicine, Oakland University, Rochester, Michigan.
Shiva Hadi EsfahaniDepartment of Foundational Medical Studies, William Beaumont School of Medicine, Oakland University, Rochester, Michigan; Department of Pharmaceutical Sciences and Brain Drug Discovery Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas.
Dhavalkumar PatelDepartment of Pharmaceutical Sciences and Brain Drug Discovery Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas.
Dennis DanneckerDepartment of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan.
Monika MaciagDepartment of Foundational Medical Studies, William Beaumont School of Medicine, Oakland University, Rochester, Michigan.
Alyssa PaulDepartment of Chemistry, Oakland University, Rochester, Michigan.
Kaitlin LowranDepartment of Chemistry, Oakland University, Rochester, Michigan.
Shikha KumariDepartment of Pharmaceutical Sciences, College of Pharmacy and Center for Drug Design and Innovation, University of Nebraska Medical Center, Omaha, Nebraska.
Samik BoseDepartment of Computational Mathematics Science and Engineering, Michigan State University, East Lansing, Michigan.
David A OstrovDepartment of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida.
Colin G WuDepartment of Chemistry, Oakland University, Rochester, Michigan.
Alex DicksonDepartment of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan; Department of Computational Mathematics Science and Engineering, Michigan State University, East Lansing, Michigan.
Thomas J AbbruscatoDepartment of Pharmaceutical Sciences and Brain Drug Discovery Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas.
Paul C TrippierDepartment of Pharmaceutical Sciences, College of Pharmacy and Center for Drug Design and Innovation, University of Nebraska Medical Center, Omaha, Nebraska.
Benjamin J OrlandoDepartment of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan.
Vardan T KaramyanDepartment of Foundational Medical Studies, William Beaumont School of Medicine, Oakland University, Rochester, Michigan; Department of Pharmaceutical Sciences and Brain Drug Discovery Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas. Electronic address: vkaramyan@oakland.edu.

Funding

Development and Characterization of Small Molecule Activators of Peptidase Neurolysin for Stroke TherapyR01NS106879 · NINDS · TEXAS TECH UNIVERSITY HEALTH SCIS CENTER · PI Thomas J Abbruscato, Vardan T. Karamyan · 2018 to 2026
$4.2M
Revealing the Ligand Binding Landscape with Advanced Molecular Simulation MethodsR01GM130794 · NIGMS · MICHIGAN STATE UNIVERSITY · PI DICKSON, ALEXANDER · 2018 to 2025
$2.8M
Exploring conformational and chemical spaces with advanced molecular simulation algorithmsR35GM161406 · NIGMS · MICHIGAN STATE UNIVERSITY · PI Alexander Dickson · 2026 to 2026
$594k
NIGMS NIH HHS R01 GM130794NIGMS NIH HHS R35 GM161406NINDS NIH HHS R01 NS106879
6 · The paper itself

Abstract

Neurolysin (Nln) is a peptidase recognized for its cerebroprotective function in acute ischemic stroke. This study aimed to identify small molecule activators of Nln as research tools to further explore the role of this enzyme in stroke and other neurological disorders. Building on our previous computational screen of ∼140,000 compounds from the National Cancer Institute Developmental Therapeutics Program database, we extended experimental testing to the top 100 candidates using an Nln enzymatic assay. A pyridine-piperazine derivative (Py-Pip) was identified as a hit molecule and was characterized in detail. Py-Pip concentration-dependently enhanced the hydrolysis of both synthetic and natural substrates (neurotensin, angiotensin I, and bradykinin) by rat Nln, and displayed comparable activating effects on human and mouse orthologs. Importantly, Py-Pip exhibited a favorable selectivity profile, showing no potentiation of homologous metallopeptidases or unrelated enzymes. Kinetic analysis revealed that Py-Pip increases the catalytic efficiency (V

Indexed as

Drug DiscoveryLysine CarboxypeptidasePiperazinesPyridinesSmall Molecule LibrariesAnimalsHumansKineticsMetalloendopeptidasesMiceRatsLysine CarboxypeptidaseMetalloendopeptidasesneurolysinPiperazinespyridinePyridinesSmall Molecule LibrariesAllosteric modulationCerebroprotectionEnzyme activatorEnzyme kineticsMetallopeptidaseNonpeptide scaffold

Identifiers

PMID41759240
PMCPMC13095470

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.