DMSO-Perturbing Assay for Identifying Promiscuous Enzyme Inhibitors

Keisuke Tomohara, Isao Adachi, Yoshikazu Horino, Hitoshi Kesamaru, Hitoshi Abe, Keitaro Suyama, Takeru Nose

Research output: Contribution to journalArticle

Abstract

In search for enzyme inhibitors, we often encounter "promiscuous" enzyme inhibitors exhibiting nonspecific binding property toward enzyme active site. Therefore, inhibitory candidates should be mechanistically characterized as early as possible in discovery processes. However, there remains a lack of highly reliable and readily available methodology to evaluate specificity of initial hits inhibitors. The present study developed and established a novel DMSO-perturbing assay to identify promiscuous enzyme inhibitors. The assay successfully identified nonspecific binding inhibitors with a broad scope, typically by the attenuation of inhibitory activity by the influence of DMSO-addition. This attenuation would be attributed to the nonspecific binding property of inhibitors toward both productive and nonproductive (nondenatured) states of enzymes in perturbation solution. This working hypothesis was supported by spectroscopic analyses of enzyme conformations and analyses of solvent effects on perturbation. Overall, these results provided a novel concept of the DMSO-perturbing assay.

Original languageEnglish
Pages (from-to)923-928
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume10
Issue number6
DOIs
Publication statusPublished - Jan 1 2019

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Enzyme Inhibitors
Dimethyl Sulfoxide
Assays
Enzymes
Conformations
Catalytic Domain

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

DMSO-Perturbing Assay for Identifying Promiscuous Enzyme Inhibitors. / Tomohara, Keisuke; Adachi, Isao; Horino, Yoshikazu; Kesamaru, Hitoshi; Abe, Hitoshi; Suyama, Keitaro; Nose, Takeru.

In: ACS Medicinal Chemistry Letters, Vol. 10, No. 6, 01.01.2019, p. 923-928.

Research output: Contribution to journalArticle

Tomohara, Keisuke ; Adachi, Isao ; Horino, Yoshikazu ; Kesamaru, Hitoshi ; Abe, Hitoshi ; Suyama, Keitaro ; Nose, Takeru. / DMSO-Perturbing Assay for Identifying Promiscuous Enzyme Inhibitors. In: ACS Medicinal Chemistry Letters. 2019 ; Vol. 10, No. 6. pp. 923-928.
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