Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 10, Issue 6, Pages 923-928Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00093
Keywords
DMSO; perturbation; enzyme inhibitor; nonspecific binding
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Funding
- JSPS KAKENHI [JP26870217, JP17K17750]
- Tamura Science and Technology Foundation
- Kanamori Foundation
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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.
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