Determining the Relative Binding Affinity of Ricin Toxin A Inhibitors by Using Molecular Docking and Nonequilibrium...

Area of Science:

• Biochemistry and Molecular Biology
• Computational Chemistry
• Toxicology

Background:

• Ricin, a potent ribosome-inactivating protein (RIP type 2), poses a significant bioterrorism threat due to its cytotoxicity.
• Inhibiting ricin toxin A (RTA), a key component, is crucial for developing countermeasures.
• Pterin derivatives show promise as potential RTA inhibitors.

Purpose of the Study:

• To evaluate pterin derivatives as RTA inhibitors using computational methods.
• To assess the correlation between nonequilibrium work and inhibitory activity (IC50) of RTA inhibitors.
• To determine the efficacy of combining molecular docking and steered molecular dynamics (SMD) for inhibitor screening.

Main Methods:

• Molecular docking was employed to predict the binding poses of RTA inhibitors.
• Fast steered molecular dynamics (SMD) simulations were performed to calculate nonequilibrium work (⟨ W⟩).
• The correlation between ⟨ W⟩ and experimental IC50 values for six RTA inhibitors was analyzed.

Main Results:

• Molecular docking effectively predicted bioactive poses for RTA inhibitors.
• A strong correlation (R² = 0.961) was observed between ⟨ W⟩ and IC50 values.
• The combined approach of docking and SMD ranked inhibitors more accurately than docking alone.

Conclusions:

• The combination of molecular docking and fast SMD simulations is a powerful tool for distinguishing active RTA inhibitors from inactive ones.
• This integrated computational strategy can serve as an effective post-docking filtering approach for inhibitor development.
• The findings support the development of pterin derivatives as potential RTA inhibitors.