Once inside the cell, ricin is subjected to retrograde transport towards the endoplasmic reticulum, where RTA and RTB are separated by the enzyme disulfide isomerase. RTB is a lectin that promotes cell entrance due to interaction with galactose-containing glycolipids and glycoproteins in the cell membrane. Ricin is classified as a type 2 RIP since it is formed by two subunits, ricin toxin A (RTA) and ricin toxin B (RTB), linked by a disulfide bridge between Cys259 of RTA and Cys4 of RTB. Since rRNA is involved in protein synthesis and elongation, the cleavage of the glycosidic bond and consequent removal of the adenine interrupts these processes and potentially leads to cell death. The removed adenine is the second nitrogenous base in the referred tetraloop, which is underlined, and corresponds to adenine 4324 (A-4324) of rat 28S rRNA. It is classified as a ribosome-inactivating protein (RIP) due to its depurination role in the eukaryotic cells, which consist of the removal of a single adenine located in the universally conserved GAGA-tetraloop structure of 28S ribosomal RNA (rRNA) of eukaryotic cells. Ricin is a toxin found in the seeds of the castor plant ( Ricinus communis), a widely spread plant in tropical regions and against which there are still no antidotes. ![]() Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculations. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes.
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