Determining the Relative Binding Affinity of Ricin Toxin A Inhibitors by Using Molecular Docking and Nonequilibrium Work

Abstract

Ricin is a ribosome-inactivating protein (RIP type 2) consisting of two subunits, ricin toxin A (RTA) and ricin toxin B (RTB). Because of its cytotoxicity, ricin has worried world authorities for its potential use as a chemical weapon; therefore, its inhibition is of great biotechnological interest. RTA is the target for inhibitor synthesis, and pterin derivatives are promising candidates to inhibit it. In this study, we used a combination of the molecular docking approach and fast steered molecular dynamics (SMD) to assess the correlation between nonequilibrium work, ⟨ W⟩, and the IC for six RTA inhibitors. The results showed that molecular docking is a powerful tool to predict good bioactive poses of RTA inhibitors, and ⟨ W⟩ presented a strong correlation with IC ( R = 0.961). Such a profile ranked the RTA inhibitors better than the molecular docking approach. Therefore, the combination of docking and fast SMD simulation was shown to be a promising tool to distinguish RTA-active inhibitors from inactive ones and could be used as postdocking filtering approach.

Thermochemical and Quantum Descriptor Calculations for Gaining Insight into Ricin Toxin A (RTA) Inhibitors

“…When comparing the Δ H bind results obtained by single-point calculations using the PM6, PM6-DH+, PM7, and RM1 methods with IC 50 experimental data for the ligands (19M, RS8, 0RB, 1MX, JP2, and JP3), we found that the PM6 method showed correlation of 0.688 and RM1 method showed no correlation with the IC 50 . On the other hand, the PM6-DH+ and PM7 methods were able to identify the 19M ligand, which has the lowest IC 50 value (15 μM), as the best ligand.…”

“…All RTA–ligand complexes were relaxed and then equilibrated using molecular dynamics simulations. We set the MD simulations according to the settings used in ref . The last frame of each MD simulation was used to calculate binding enthalpies using semiempirical quantum mechanical (SQM) methods considering two scenarios: (i) a direct single-point energy calculation with RM1, PM6, PM6-DH+, PM6-D3H4, and PM7 and (ii) after full-atom geometry optimization with PM6-DH+, PM6-D3H4, and PM7.…”

“…Knowledge of the intermolecular interactions of protein–ligand systems is an important feature for the development of new drugs . In this way, some approaches, e.g., molecular docking, have been used to predict the bioactive pose of ligands in the active sites of biological targets with therapeutic interest; however, it is quite ineffective to predict the relative binding affinity and rank ligands according to experimental data. ,, …”

Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors

“…These interactions can be exploited towards the discovery of antidotes to toxic proteins, drugs against pathogens, or modulators in the human body [19,[31][32][33]. It is also possible to use cheminformatics aiming clarification and explanation of obtained or existing experimental results [15,34,35]. The application of these studies towards the development of toxin inhibitors has the additional advantage regarding safety, since they have the potential to diminish the need of dealing with toxic substances in early research stages.…”

Structural Stability Predicts the Binding Mode of Protein–Ligand Complexes

“…Moreover, many methods are based on a static representation of biomolecules forced by X-ray structures, and the influence of protein flexibility on binding cannot be underestimated. , Alternative approaches to improve binding mode prediction have been described in the literature. Some apply methods with a better theoretical background to rescore a subset of poses. − Others carry out molecular dynamics (MD) simulations of the complex to confirm that the predicted binding mode is stable − or to explore drug–target binding event fully. , Significant improvements in accuracy and reliability of predictions have been made by coupling induced-fit docking with stability assessment of the pose by metadynamics . However, there is still room for improvement, and orthogonal methods that could complement the existing ones would be particularly useful.…”