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Discovery of Potent Succinate-Ubiquinone Oxidoreductase Inhibitors via Pharmacophore-linked Fragment Virtual Screening Approach.
- Source :
-
Journal of agricultural and food chemistry [J Agric Food Chem] 2016 Jun 22; Vol. 64 (24), pp. 4830-7. Date of Electronic Publication: 2016 Jun 08. - Publication Year :
- 2016
-
Abstract
- Succinate-ubiquinone oxidoreductase (SQR) is an attractive target for fungicide discovery. Herein, we report the discovery of novel SQR inhibitors using a pharmacophore-linked fragment virtual screening approach, a new drug design method developed in our laboratory. Among newly designed compounds, compound 9s was identified as the most potent inhibitor with a Ki value of 34 nM against porcine SQR, displaying approximately 10-fold higher potency than that of the commercial control penthiopyrad. Further inhibitory kinetics studies revealed that compound 9s is a noncompetitive inhibitor with respect to the substrate cytochrome c and DCIP. Interestingly, compounds 8a, 9h, 9j, and 9k exhibited good in vivo preventive effects against Rhizoctonia solani. The results obtained from molecular modeling showed that the orientation of the R(2) group had a significant effect on binding with the protein.
- Subjects :
- Drug Discovery
Electron Transport Complex II chemistry
Electron Transport Complex II metabolism
Enzyme Inhibitors pharmacology
Fungi drug effects
Fungicides, Industrial chemistry
Fungicides, Industrial pharmacology
Kinetics
Models, Molecular
Succinic Acid
Electron Transport Complex II antagonists & inhibitors
Enzyme Inhibitors chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-5118
- Volume :
- 64
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Journal of agricultural and food chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 27225833
- Full Text :
- https://doi.org/10.1021/acs.jafc.6b00325