Identification of novel potential ricin inhibitors by virtual screening, molecular docking, molecular dynamics and MM-PBSA calculations: a drug repurposing approach

Abstract

Ricin is a potent cytotoxin with no available antidote. Its catalytic subunit, RTA, damages the ribosomal RNA (rRNA) of eukaryotic cells, preventing protein synthesis and eventually leading to cell death. The combination between easiness of obtention and high toxicity turns ricin into a potential weapon for terrorist attacks, urging the need of discovering effective antidotes. On this context, we used computational techniques, in order to identify potential ricin inhibitors among approved drugs. Two libraries were screened by two different docking algorithms, followed by molecular dynamics simulations and MM-PBSA calculations in order to corroborate the docking results. Three drugs were identified as potential ricin inhibitors: deferoxamine, leucovorin and plazomicin. Our calculations showed that these compounds were able to, simultaneously, form hydrogen bonds with residues of the catalytic site and the secondary binding site of RTA, qualifying as potential antidotes against intoxication by ricin.

Communicated by Ramaswamy H. Sarma

Keywords:

• Ricin inhibitors
• drug repurposing
• biological warfare agents
• ricin
• virtual screening

Acknowledgements

The authors wish to thank the financial support of the Brazilian agencies Conselho Nacional de Pesquisa (CNPq), grant number 308225/2018–0; Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), grant number E-02/202.961/2017; IFES—PRPPG, grant number 10/2019 (Productivity Researcher Program PPP); and FAPES, grant number 03/2020-2020-WMT5F. This work was also supported by the University of Hradec Králové. We also thank the Federal University of Lavras (UFLA) for software facilities, and Dr. Raphael Silva for help with the identification of molecules with possible dangerous side effects that were excluded before docking simulations.

Disclosure statement

The authors declare no potential conflict of interest.

Additional information

Funding

Conselho Nacional de Desenvolvimento Científico e Tecnológico; Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro.