Early identification of promiscuous attributes of aldose reductase inhibitors using a DMSO-perturbation assay

Keisuke Tomohara, Naoto Hasegawa, Isao Adachi, Yoshikazu Horino, Takeru Nose

Research output: Contribution to journalArticle

Abstract

Aldose reductase (AR) inhibitors are used clinically to treat long-term diabetic complications. Previous studies reported a series of AR inhibitory candidates, but unfortunately the mode of inhibition was poorly described due mainly to the lack of readily available methods for evaluating the specificity. The present study examined the AR inhibitory effects of novel synthetic hydantoins and their structural relatives, some of which were obtained from chemically engineered extracts of natural plants, and discovered several novel AR inhibitors with moderate inhibitory activity. The identified inhibitors were then subjected to a two-step mechanistic characterization using a detergent-addition assay and our novel dimethyl sulfoxide (DMSO)-perturbation assay. The detergent-addition assay revealed aggregation-based inhibitors, and the subsequent DMSO-perturbation assay identified nonspecific binding inhibitors. Thus, the present study demonstrates the usefulness of the DMSO-perturbation screen for identifying nonspecific binding characteristics of AR inhibitors.

Original languageEnglish
Article number126815
JournalBioorganic and Medicinal Chemistry Letters
Volume30
Issue number2
DOIs
Publication statusPublished - Jan 15 2020

Fingerprint

Aldehyde Reductase
Dimethyl Sulfoxide
Assays
Detergents
Hydantoins
Plant Extracts
Diabetes Complications
Agglomeration

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Early identification of promiscuous attributes of aldose reductase inhibitors using a DMSO-perturbation assay. / Tomohara, Keisuke; Hasegawa, Naoto; Adachi, Isao; Horino, Yoshikazu; Nose, Takeru.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 30, No. 2, 126815, 15.01.2020.

Research output: Contribution to journalArticle

@article{373ecf2dc44a437c8036078788de4fa8,
title = "Early identification of promiscuous attributes of aldose reductase inhibitors using a DMSO-perturbation assay",
abstract = "Aldose reductase (AR) inhibitors are used clinically to treat long-term diabetic complications. Previous studies reported a series of AR inhibitory candidates, but unfortunately the mode of inhibition was poorly described due mainly to the lack of readily available methods for evaluating the specificity. The present study examined the AR inhibitory effects of novel synthetic hydantoins and their structural relatives, some of which were obtained from chemically engineered extracts of natural plants, and discovered several novel AR inhibitors with moderate inhibitory activity. The identified inhibitors were then subjected to a two-step mechanistic characterization using a detergent-addition assay and our novel dimethyl sulfoxide (DMSO)-perturbation assay. The detergent-addition assay revealed aggregation-based inhibitors, and the subsequent DMSO-perturbation assay identified nonspecific binding inhibitors. Thus, the present study demonstrates the usefulness of the DMSO-perturbation screen for identifying nonspecific binding characteristics of AR inhibitors.",
author = "Keisuke Tomohara and Naoto Hasegawa and Isao Adachi and Yoshikazu Horino and Takeru Nose",
year = "2020",
month = "1",
day = "15",
doi = "10.1016/j.bmcl.2019.126815",
language = "English",
volume = "30",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "2",

}

TY - JOUR

T1 - Early identification of promiscuous attributes of aldose reductase inhibitors using a DMSO-perturbation assay

AU - Tomohara, Keisuke

AU - Hasegawa, Naoto

AU - Adachi, Isao

AU - Horino, Yoshikazu

AU - Nose, Takeru

PY - 2020/1/15

Y1 - 2020/1/15

N2 - Aldose reductase (AR) inhibitors are used clinically to treat long-term diabetic complications. Previous studies reported a series of AR inhibitory candidates, but unfortunately the mode of inhibition was poorly described due mainly to the lack of readily available methods for evaluating the specificity. The present study examined the AR inhibitory effects of novel synthetic hydantoins and their structural relatives, some of which were obtained from chemically engineered extracts of natural plants, and discovered several novel AR inhibitors with moderate inhibitory activity. The identified inhibitors were then subjected to a two-step mechanistic characterization using a detergent-addition assay and our novel dimethyl sulfoxide (DMSO)-perturbation assay. The detergent-addition assay revealed aggregation-based inhibitors, and the subsequent DMSO-perturbation assay identified nonspecific binding inhibitors. Thus, the present study demonstrates the usefulness of the DMSO-perturbation screen for identifying nonspecific binding characteristics of AR inhibitors.

AB - Aldose reductase (AR) inhibitors are used clinically to treat long-term diabetic complications. Previous studies reported a series of AR inhibitory candidates, but unfortunately the mode of inhibition was poorly described due mainly to the lack of readily available methods for evaluating the specificity. The present study examined the AR inhibitory effects of novel synthetic hydantoins and their structural relatives, some of which were obtained from chemically engineered extracts of natural plants, and discovered several novel AR inhibitors with moderate inhibitory activity. The identified inhibitors were then subjected to a two-step mechanistic characterization using a detergent-addition assay and our novel dimethyl sulfoxide (DMSO)-perturbation assay. The detergent-addition assay revealed aggregation-based inhibitors, and the subsequent DMSO-perturbation assay identified nonspecific binding inhibitors. Thus, the present study demonstrates the usefulness of the DMSO-perturbation screen for identifying nonspecific binding characteristics of AR inhibitors.

UR - http://www.scopus.com/inward/record.url?scp=85075417190&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075417190&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2019.126815

DO - 10.1016/j.bmcl.2019.126815

M3 - Article

C2 - 31744675

AN - SCOPUS:85075417190

VL - 30

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 2

M1 - 126815

ER -