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
N1 - Funding Information:
This research was supported by the JSPS KAKENHI Grant Numbers JP26870217 and JP17K17750 , Kanamori Foundation , and Tamura Science and Technology Foundation. Appendix A
Funding Information:
This research was supported by the JSPS KAKENHI Grant Numbers JP26870217 and JP17K17750, Kanamori Foundation, and Tamura Science and Technology Foundation.
Publisher Copyright:
© 2019 Elsevier Ltd
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.
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U2 - 10.1016/j.bmcl.2019.126815
DO - 10.1016/j.bmcl.2019.126815
M3 - Article
C2 - 31744675
AN - SCOPUS:85075417190
SN - 0960-894X
VL - 30
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 2
M1 - 126815
ER -
