Parallel screening and cheminformatics modeling of flavonoid activated aptasensors

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Artificial riboswitches are engineered RNA molecules that can bind to specific small molecules, acting as sensors.
• Understanding ligand-riboswitch interactions is crucial for developing novel therapeutic and diagnostic tools.
• Flavonoids, a diverse group of plant metabolites, are known to interact with various biological targets.

Purpose of the Study:

• To investigate the physicochemical properties of flavonoids that dictate their binding specificity to artificial naringenin-activated riboswitches.
• To develop quantitative structure-property relationship (QSPR) models for predicting flavonoid-riboswitch interactions.
• To guide the rational design of novel ligands with enhanced binding affinity and specificity for RNA aptamers.

Main Methods:

• Parallel screening of 27 flavonoids and chalcones against 6 artificial riboswitches (M1, M2, M3, O, L, H).
• Utilized a quantitative structure-property relationship (QSPR) approach correlating molecular descriptors with fluorescence intensity.
• Developed predictive QSPR models for riboswitches M1, M2, and O using statistically significant descriptors.

Main Results:

• Electronegativity and hydrophilicity of flavonoids were identified as key properties enhancing binding affinity to RNA riboswitches.
• Specific hydroxyl group positioning (C-3' and C-4') on the flavonoid B-ring was essential for ligand activation of riboswitches M1 and M2.
• Riboswitches O and L showed a preference for multi-hydroxylated flavones, while A-ring substitutions and O-glycosylation did not significantly influence recognition.

Conclusions:

• Physicochemical properties, particularly electronegativity, hydrophilicity, and specific hydroxyl group placement, are critical determinants of flavonoid binding to artificial riboswitches.
• The developed QSPR models provide valuable insights into the molecular recognition mechanisms of RNA-ligand interactions.
• This study facilitates the design of high-specificity ligands for conformational structural studies and the development of advanced aptamer-based technologies.