Discovery of novel regulators of aldehyde dehydrogenase isoenzymes

Bibek Parajuli, Ann C. Kimble-Hill, May Khanna, Yvelina Ivanova, Samy Meroueh, Thomas Hurley

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Over the past three years we have been involved in high-throughput screening in an effort to discover novel small molecular modulators of aldehyde dehydrogenase (ALDH) activity. In particular, we have been interested in both the activation and inhibition of the three commonly studied isoenzymes, ALDH1A1, ALDH2 and ALDH3A1, as their distinct, yet overlapping substrate specificities, present a particularly difficult challenge for inhibitor discovery and design. Activation of ALDH2 has been shown to benefit cardiovascular outcome following periods of ischemia and renewed interest in specific inhibition of ALDH2 has application for alcohol aversion therapy, and more recently, in cocaine addiction. In contrast, inhibition of either ALDH1A1 or ALDH3A1 has application in cancer treatments where the isoenzymes are commonly over-expressed and serve as markers for cancer stem cells. We are taking two distinct approaches for these screens: in vitro enzyme activity screens using chemical libraries and virtual computational screens using the structures of the target enzymes as filters for identifying potential inhibitors, followed by in vitro testing of their ability to inhibit their intended targets. We have identified selective inhibitors of each of these three isoenzymes with inhibition constants in the high nanomolar to low micromolar range from these screening procedures. Together, these inhibitors provide proof for concept that selective inhibition of these broad specificity general detoxication enzymes through small molecule discovery and design is possible.

Original languageEnglish
Pages (from-to)153-158
Number of pages6
JournalChemico-Biological Interactions
Volume191
Issue number1-3
DOIs
StatePublished - May 30 2011

Fingerprint

Aldehyde Dehydrogenase
Isoenzymes
Screening
Chemical activation
Oncology
Enzyme activity
Enzymes
Stem cells
Cocaine
Aversive Therapy
Modulators
Small Molecule Libraries
Cocaine-Related Disorders
Alcohols
Throughput
Aptitude
Neoplastic Stem Cells
Substrate Specificity
Molecules
Testing

Keywords

  • Aldehyde dehydrogenase
  • Computational docking
  • High-throughput screening

ASJC Scopus subject areas

  • Toxicology

Cite this

Discovery of novel regulators of aldehyde dehydrogenase isoenzymes. / Parajuli, Bibek; Kimble-Hill, Ann C.; Khanna, May; Ivanova, Yvelina; Meroueh, Samy; Hurley, Thomas.

In: Chemico-Biological Interactions, Vol. 191, No. 1-3, 30.05.2011, p. 153-158.

Research output: Contribution to journalArticle

Parajuli, Bibek ; Kimble-Hill, Ann C. ; Khanna, May ; Ivanova, Yvelina ; Meroueh, Samy ; Hurley, Thomas. / Discovery of novel regulators of aldehyde dehydrogenase isoenzymes. In: Chemico-Biological Interactions. 2011 ; Vol. 191, No. 1-3. pp. 153-158.
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