Design, Synthesis, and Characterization of Sulfamide and Sulfamate Nucleotidomimetic Inhibitors of hHint1

Rachit Shah, Alexander Strom, Andrew Zhou, Kimberly M Maize, Barry C Finzel, Carston R Wagner

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Hint1 has recently emerged to be an important target of interest due to its involvement in the regulation of a broad range of CNS functions including opioid signaling, tolerance, neuropathic pain, and nicotine dependence. A series of inhibitors were rationally designed, synthesized, and tested for their inhibitory activity against hHint1 using isothermal titration calorimetry (ITC). The studies resulted in the development of the first small-molecule inhibitors of hHint1 with submicromolar binding affinities. A combination of thermodynamic and high-resolution X-ray crystallographic studies provides an insight into the biomolecular recognition of ligands by hHint1. These novel inhibitors have potential utility as molecular probes to better understand the role and function of hHint1 in the CNS.

Original languageEnglish (US)
Pages (from-to)780-784
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume7
Issue number8
DOIs
StatePublished - Aug 11 2016

Fingerprint

Molecular Probes
Tobacco Use Disorder
Calorimetry
Neuralgia
Thermodynamics
Opioid Analgesics
X-Rays
Ligands
Titration
Nicotine
X rays
Molecules
sulfamic acid

Keywords

  • CNS
  • ITC
  • central nervous system
  • hHint1
  • human histidine triad nucleotide binding protein 1
  • isothermal titration calorimetry

Cite this

Design, Synthesis, and Characterization of Sulfamide and Sulfamate Nucleotidomimetic Inhibitors of hHint1. / Shah, Rachit; Strom, Alexander; Zhou, Andrew; Maize, Kimberly M; Finzel, Barry C; Wagner, Carston R.

In: ACS Medicinal Chemistry Letters, Vol. 7, No. 8, 11.08.2016, p. 780-784.

Research output: Contribution to journalArticle

@article{54638a8f6947471196d00595e0f7f330,
title = "Design, Synthesis, and Characterization of Sulfamide and Sulfamate Nucleotidomimetic Inhibitors of hHint1",
abstract = "Hint1 has recently emerged to be an important target of interest due to its involvement in the regulation of a broad range of CNS functions including opioid signaling, tolerance, neuropathic pain, and nicotine dependence. A series of inhibitors were rationally designed, synthesized, and tested for their inhibitory activity against hHint1 using isothermal titration calorimetry (ITC). The studies resulted in the development of the first small-molecule inhibitors of hHint1 with submicromolar binding affinities. A combination of thermodynamic and high-resolution X-ray crystallographic studies provides an insight into the biomolecular recognition of ligands by hHint1. These novel inhibitors have potential utility as molecular probes to better understand the role and function of hHint1 in the CNS.",
keywords = "CNS, ITC, central nervous system, hHint1, human histidine triad nucleotide binding protein 1, isothermal titration calorimetry",
author = "Rachit Shah and Alexander Strom and Andrew Zhou and Maize, {Kimberly M} and Finzel, {Barry C} and Wagner, {Carston R}",
year = "2016",
month = "8",
day = "11",
doi = "10.1021/acsmedchemlett.6b00169",
language = "English (US)",
volume = "7",
pages = "780--784",
journal = "ACS Medicinal Chemistry Letters",
issn = "1948-5875",
publisher = "American Chemical Society",
number = "8",

}

TY - JOUR

T1 - Design, Synthesis, and Characterization of Sulfamide and Sulfamate Nucleotidomimetic Inhibitors of hHint1

AU - Shah, Rachit

AU - Strom, Alexander

AU - Zhou, Andrew

AU - Maize, Kimberly M

AU - Finzel, Barry C

AU - Wagner, Carston R

PY - 2016/8/11

Y1 - 2016/8/11

N2 - Hint1 has recently emerged to be an important target of interest due to its involvement in the regulation of a broad range of CNS functions including opioid signaling, tolerance, neuropathic pain, and nicotine dependence. A series of inhibitors were rationally designed, synthesized, and tested for their inhibitory activity against hHint1 using isothermal titration calorimetry (ITC). The studies resulted in the development of the first small-molecule inhibitors of hHint1 with submicromolar binding affinities. A combination of thermodynamic and high-resolution X-ray crystallographic studies provides an insight into the biomolecular recognition of ligands by hHint1. These novel inhibitors have potential utility as molecular probes to better understand the role and function of hHint1 in the CNS.

AB - Hint1 has recently emerged to be an important target of interest due to its involvement in the regulation of a broad range of CNS functions including opioid signaling, tolerance, neuropathic pain, and nicotine dependence. A series of inhibitors were rationally designed, synthesized, and tested for their inhibitory activity against hHint1 using isothermal titration calorimetry (ITC). The studies resulted in the development of the first small-molecule inhibitors of hHint1 with submicromolar binding affinities. A combination of thermodynamic and high-resolution X-ray crystallographic studies provides an insight into the biomolecular recognition of ligands by hHint1. These novel inhibitors have potential utility as molecular probes to better understand the role and function of hHint1 in the CNS.

KW - CNS

KW - ITC

KW - central nervous system

KW - hHint1

KW - human histidine triad nucleotide binding protein 1

KW - isothermal titration calorimetry

UR - http://www.scopus.com/inward/record.url?scp=84982102990&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84982102990&partnerID=8YFLogxK

U2 - 10.1021/acsmedchemlett.6b00169

DO - 10.1021/acsmedchemlett.6b00169

M3 - Article

VL - 7

SP - 780

EP - 784

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 8

ER -