The concept of drug-likeness has been established in the field of drug discovery. Pesticide discovery is also a complicated and rigorous filtering process compared with drug discovery. This study involved investigation of the constitutive properties of 788 marketed pesticides, including 341 herbicides, 182 fungicides, and 265 insecticides. In a comparison of the constitutive properties of different kinds of pesticides and of pesticides from different periods of registration, ClogP, the number of H-bond donors (HBD), and the number of aromatic bonds (ARB) were identified as the most important factors that distinguish herbicides, fungicides, and insecticides. In addition, the reduction in pesticide toxicity with revolution time was found to have some relationship with an increase in values of the six constitutive properties. Finally, we established some rules for pesticide-likeness, including molecular weight≤435 Da, ClogP≤6, number of H-bond acceptors (HBA)≤6, HBD≤2, number of rotatable bonds (ROB)≤9, and ARB≤17. The constitutive property-related novel findings in this study will promote the structure-based optimization of pesticide candidates.
Selenocysteine (Sec), encoded as the 21st amino acid, is the predominant chemical form of selenium that is closely related to various human diseases. Thus, it is of high importance to identify novel probes for sensitive and selective recognition of Sec and Sec-containing proteins. Although a few probes have been reported to detect artificially introduced selenols in cells or tissues, none of them has been shown to be sensitive enough to detect endogenous selenols. We report the characterization and application of a new fluorogenic molecular probe for the detection of intracellular selenols. This probe exhibits near-zero background fluorescence but produces remarkable fluorescence enhancement upon reacting with selenols in a fast chemical reaction. It is highly specific and sensitive for intracellular selenium-containing molecules such as Sec and selenoproteins. When combined with flow cytometry, this probe is able to detect endogenous selenols in various human cancer cells. It is also able to image endogenous selenol-containing molecules in zebrafish under a fluorescence microscope. These results demonstrate that this molecular probe can function as a useful molecular tool for intracellular selenol sensing, which is valuable in the clinical diagnosis for human diseases associated with Sec-deficiency or overdose.
Human neutrophil elastase (HNE) has been identified as a potential therapeutic target for the discovery of anti-inflammatory drugs for decades. However, little progress has been made on assays measuring the activity of HNE, especially on synthetic substrates which play essential role in determination of HNE activity. Herein, a small-molecule compound, 2,2,3,3,3-pentafluoro-N-(2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)-propanamide (compound 4), has been successfully designed as the first ever non-peptide-based fluorogenic substrate for HNE. A "turn-on" fluorometric assay based on 4 has been successfully developed for rapid determination of HNE activity and the inhibitory kinetic study. Most importantly, the probe 4 shows highly specific response for HNE among seven tested hydrolases or proteins and can be directly used to detect the elevated HNE activity in the serum of chronic obstructive pulmonary disease (COPD) patients compared to that of healthy controls. This specific and cost-effective probe will facilitate future high-throughput discovery of HNE inhibitors and clinical diagnosis of elastase-related diseases.
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