Accuracy assessment of protein-based docking programs against RNA targets

Area of Science:

• Computational Chemistry
• Structural Biology
• Drug Discovery

Background:

• Ribonucleic acid (RNA) molecules are crucial in biological processes and represent promising therapeutic targets.
• Molecular docking is a key drug discovery technique, but existing programs are primarily designed for proteins, not RNA.
• The suitability of protein-based docking software for RNA targets remains underexplored.

Purpose of the Study:

• To comprehensively evaluate the accuracy of two popular protein-based docking programs, GOLD and Glide, for RNA targets.
• To assess the utility of these programs in virtual screening and fragment-based drug design for RNA.

Main Methods:

• Evaluated GOLD 4.0 and Glide 5.0 using multiple docking strategies against 60 RNA complexes.
• Assessed docking and virtual screening accuracies.
• Performed simulated virtual and fragment screening experiments against the 16S rRNA A-site.

Main Results:

• Both GOLD and Glide successfully reproduced the binding modes for the majority of the tested RNA complexes.
• Significant enrichment was achieved in virtual screening and fragment screening experiments using various docking/scoring combinations.
• The 16S ribosomal RNA (rRNA) A-site was effectively targeted in screening experiments.

Conclusions:

• Protein-based docking programs like GOLD and Glide are capable of performing general docking tasks for RNA.
• These computational tools demonstrate significant potential to aid in RNA-based drug discovery and design.
• The findings support the application of established docking software in the emerging field of RNA-targeted therapeutics.