In Silico Discovery of Group II Intron RNA Splicing Inhibitors.

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Group II introns are mobile genetic elements with complex self-splicing mechanisms.
• Targeting these introns offers a potential strategy for antimicrobial drug development.

Purpose of the Study:

• To discover small molecules that inhibit the catalytic activity of group II introns.
• To explore the potential of computational methods for identifying RNA-targeting compounds.

Main Methods:

• Utilized molecular docking to screen a library of lead-like compounds against the active site of the *Oceanobacillus iheyensis* group IIC intron.
• Performed *in vitro* splicing assays to validate the inhibitory activity of identified compounds.
• Tested lead compounds against a different class of group II intron (yeast ai5γ IIB).

Main Results:

• Identified three unique chemical scaffolds that inhibit group II intron splicing *in vitro*.
• An analog of the lead scaffold demonstrated intron-dependent inhibition.
• This analog also showed activity against a phylogenetically distinct group II intron from yeast.

Conclusions:

• The identified compounds are effective inhibitors of group II intron self-splicing.
• These inhibitors represent promising chemical tools for developing novel antifungal agents.
• In silico screening is a viable approach for discovering bioactive molecules targeting complex RNA structures.