Obtenção de inibidores da subunidade catalítica da ricina, RTA, usando métodos de modelagem molecular

Abstract

Ricin is a potent toxin isolated from the castor bean plant and consists of two subunits, RTA and RTB. Because of its toxicity, ricin has alarm world authorities for its potential use as a chemical weapon. Ricin also impacts castor bean agribusiness, given the risk of animal and human poisoning. Over the years, many groups attempted to proposed small-molecules that bind to the RTA active site, the catalytic chain. Despite such efforts, there is still no effective countermeasure against ricin poisoning. The computational study carried out in the present work renewing the discussion about small-molecules that may inhibit this toxin. Here, a structure-based virtual screening protocol capable of discerning active RTA inhibitors from inactive ones was employed to screening more than 2 million compounds from the ZINC database to find novel scaffolds that strongly bind into the active site of the RTA. Besides, a novel score method based on ligand undocking force profiles and semi-empirical quantum chemical calculations provided insights into the rescore of docking poses. Summing up, the filtering steps pointed out to 7 main compounds, with the SCF00–451 as a promising candidate to inhibit the killing activity of such potent phytotoxin.