Theoretical investigation of covalent inhibitors targeting ricin

Abstract

Ricin is a highly potent toxin derived from the seeds of the castor plant (Ricinus communis). Its extreme toxicity, ease of extraction, water solubility, and the absence of an effective antidote have led to its classification as a chemical warfare agent under Schedule 1A (“Toxic Chemicals”) of the Chemical Weapons Convention. Concerns about ricin poisoning extend beyond deliberate acts, such as those linked to terrorist attacks, to include accidental exposures—particularly among workers involved in castor oil production and individuals who inadvertently ingest castor seeds. These risks underscore the urgent need for an effective antidote and have driven substantial research in this area. In this study, we present a novel approach targeting the catalytic subunit of ricin (RTA) using covalent inhibitors identified through computational methods. Virtual screening of nearly 80 000 commercially available covalent ligands, followed by covalent docking and successive rounds of molecular dynamics simulations, led to the identification of three potential covalent binders to Ser176 in the RTA active site. Our calculations indicate that these compounds can successfully form covalent bonds with the target residue. Moreover, they demonstrate stability within the RTA binding pocket prior to bond formation, further supporting their potential as effective covalent inhibitors.