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

Abstract

Ricin is a potent toxin derived from the castor bean plant and comprises two subunits, RTA and RTB. Because of its cytotoxicity, ricin has alarmed world authorities for its potential use as a chemical weapon. Ricin also affects castor bean agribusiness, given the risk of animal and human poisoning. Over the years, many groups attempted to propose 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 renews 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 performed to screen over 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 seven main compounds, with the SCF00-451 as a promising candidate to inhibit the killing activity of such potent phytotoxin.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• Ricin A-chain
• non-equilibrium work
• quantum chemistry
• virtual screening
• molecular dynamics
• pharmacophore modeling
• molecular docking

Acknowledgements

The authors thank to the Centro Nacional de Processamento de Alto Desempenho do estado de São Paulo (CENAPAD-SP) and Versatus HPC (High Performance Computing) for support in the computational resources used in this study. The authors also thank to OpenEye Scientific to provide the free academic license for their software and script package.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contribution

E.J.F.C.: Conceptualization of this study, Performed the research, Data Curation, Wrote the original draft; L.E.G.C.: Conceptualization of the semi-empirical quantum calculations on MOPAC; I.Q.M.P.: Reviewed the original draft; C.H.S.: Conceptualization of this study and reviewed the original draft; D.A.M.A.: Co-ordinator, Reviewed the original draft; G.B.R.: Cordinator, Conceptualization of this study and reviewed the original draft.

Additional information

Funding

This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) under grant 51/2013, AUXPE1375/2014/CAPES # 1; Brazilian National Council for Scientific and Technological Development under grants 309761/2017-4 # 2, 309921/2015-5 # 3 and 309921/2015-5 # 4.