Discovery of RTA ricin subunit inhibitors: a computational study using PM7 quantum chemical method and steered...

Area of Science:

• Biochemistry
• Toxicology
• Computational Chemistry

Background:

• Ricin is a highly toxic protein from castor beans, posing risks as a chemical weapon and in agriculture.
• Existing countermeasures against ricin poisoning are limited, despite efforts to find small-molecule inhibitors targeting the RTA subunit.

Purpose of the Study:

• To identify novel small-molecule scaffolds that can effectively inhibit the catalytic RTA subunit of ricin.
• To develop and apply a computational screening protocol for discovering potential ricin inhibitors.

Main Methods:

• Structure-based virtual screening of over 2 million compounds from the ZINC database against the ricin RTA active site.
• Development of a novel rescoring method using ligand undocking force profiles and quantum chemical calculations.

Main Results:

• The screening protocol successfully identified seven promising compounds with potential to inhibit ricin.
• Compound SCF00-451 emerged as a particularly strong candidate for inhibiting ricin's toxic activity.

Conclusions:

• Computational approaches can effectively identify novel inhibitors for potent toxins like ricin.
• The identified compounds, especially SCF00-451, warrant further investigation as potential therapeutic agents against ricin poisoning.