DMSO-Perturbing Assay for Identifying Promiscuous Enzyme Inhibitors

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

研究成果: ジャーナルへの寄稿記事

抄録

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.

元の言語英語
ページ(範囲)923-928
ページ数6
ジャーナルACS Medicinal Chemistry Letters
10
発行部数6
DOI
出版物ステータス出版済み - 1 1 2019

Fingerprint

Enzyme Inhibitors
Dimethyl Sulfoxide
Assays
Enzymes
Conformations
Catalytic Domain

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

これを引用

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

:: ACS Medicinal Chemistry Letters, 巻 10, 番号 6, 01.01.2019, p. 923-928.

研究成果: ジャーナルへの寄稿記事

Tomohara, Keisuke ; Adachi, Isao ; Horino, Yoshikazu ; Kesamaru, Hitoshi ; Abe, Hitoshi ; Suyama, Keitaro ; Nose, Takeru. / DMSO-Perturbing Assay for Identifying Promiscuous Enzyme Inhibitors. :: ACS Medicinal Chemistry Letters. 2019 ; 巻 10, 番号 6. pp. 923-928.
@article{0ed576a2944b4a6dbad5b45cb80a34aa,
title = "DMSO-Perturbing Assay for Identifying Promiscuous Enzyme Inhibitors",
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.",
author = "Keisuke Tomohara and Isao Adachi and Yoshikazu Horino and Hitoshi Kesamaru and Hitoshi Abe and Keitaro Suyama and Takeru Nose",
year = "2019",
month = "1",
day = "1",
doi = "10.1021/acsmedchemlett.9b00093",
language = "English",
volume = "10",
pages = "923--928",
journal = "ACS Medicinal Chemistry Letters",
issn = "1948-5875",
publisher = "American Chemical Society",
number = "6",

}

TY - JOUR

T1 - DMSO-Perturbing Assay for Identifying Promiscuous Enzyme Inhibitors

AU - Tomohara, Keisuke

AU - Adachi, Isao

AU - Horino, Yoshikazu

AU - Kesamaru, Hitoshi

AU - Abe, Hitoshi

AU - Suyama, Keitaro

AU - Nose, Takeru

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85066905926&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066905926&partnerID=8YFLogxK

U2 - 10.1021/acsmedchemlett.9b00093

DO - 10.1021/acsmedchemlett.9b00093

M3 - Article

AN - SCOPUS:85066905926

VL - 10

SP - 923

EP - 928

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 6

ER -