Cyanobacterial
fructose-1,6-/sedoheptulose-1,7-bisphosphatase (Cy-FBP/SBPase)
was an important regulatory enzyme in cyanobacterial photosynthesis
and was a potential target enzyme for screening to obtain novel inhibitors
against cyanobacterial blooms. In this study, we developed a novel
pharmacophore screening model based on the catalytic mechanism and
substrate structure of Cy-FBP/SBPase and screened 26 S series compounds with different structures and pharmacophore characteristics
from the Specs database by computer-assisted drug screening. These
compounds exhibited moderate inhibitory activity against Cy-FBP/SBPase,
with 9 compounds inhibiting >50% at 100 μM. Among them, compound S5 showed excellent inhibitory activity against both Cy-FBP/SBPase
and Synechocystis sp. PCC6803 (IC50 = 6.7 ± 0.7 μM and EC50 = 7.7 ±
1.4 μM). The binding mode of compound S5 to Cy-FBP/SBPase
was predicted using the molecular docking theory and validated by
sentinel mutation and enzyme activity analysis. Physiochemical, gene
transcription level, and metabolomic analyses showed that compound S5 significantly reduced the quantum yield of photosystem
II and the maximum electron transfer rate, downregulated transcript
levels of related genes encoding the Calvin cycle and photosystem,
reduced the photosynthetic efficiency of cyanobacteria, thus inhibited
metabolic pathways, such as the Calvin cycle and tricarboxylic acid
cycle, and eventually achieved an efficient algicide. In addition,
compound S5 had a high safety profile for human-derived
cells and zebrafish. In summary, the novel pharmacophore screening
model obtained from the current work provides an effective solution
to the cyanobacterial bloom problem.
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