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

Theoretical Investigation of Repurposed Drugs Potentially Capable of Binding to the Catalytic Site and the Secondary Binding Pocket of Subunit A of Ricin

“…As mentioned in the Introduction, we studied in this work the 6 molecules pointed before as potential antidotes against ricin ( Figure S2 ) 13 plus 9 additional compounds ( Figure 2 ) originally selected by VS and pointed by docking studies as potential dual binders to RTA, but not investigated through MD simulations. By extending the study to these 9 compounds, we advanced one more step toward the ultimate goal of investigating through MD simulations the whole library of 82 compounds formerly selected by VS. 13 These 9 compounds were selected based on a visual inspection to ensure a structural diversity that represents the most of the whole library.…”

“…Here, the MM-PBSA calculations were performed as before 13 using the g_mmpbsa tool, compatible with GROMACS 2019.4 software. 18 For this, it was necessary first to run 100 ns of MD simulation of the best poses of the ligands inside RTA obtained in the docking studies in order to afford the trajectory frames needed to feed the g_mmpbsa tool.…”

“…Recently, we proposed the repurposing approach as a promising strategy to follow in the search for more effective antidotes against ricin intoxication capable of binding into both the catalytic site and the secondary pocket of RTA. 13 On this line, we performed virtual screening (VS) searches in the FDA-approved drugs data set, available at Cheminfo ( ), the approved drugs library available at DrugBank ( ), and the PubChem database ( ). This search enabled the selection of 6795 potential binders to RTA which, after additional refinements, including drug-likeness, afforded a library of 82 compounds.…”

“…Further molecular dynamics (MD) simulations on the first 15 compounds selected from this library enabled pointing 6 ( Figure S2 ) as potential antidotes against RTA. 13 Here, we moved forward on the investigation of this library through additional theoretical studies on the 6 molecules shown in Figure S2 plus 9 more selected compounds ( Figure 2 ). Flexible docking of these compounds enabled drawing their fingerprints inside RTA and plotting the most important residues for the ligand binding.…”

Identification of Novel Inhibitors of Type-I Mycobacterium Tuberculosis Fatty Acid Synthase Using Docking-Based Virtual Screening and Molecular Dynamics Simulation

“…The MM/PBSA approach has been reported to be applied reliably for re-scoring the protein-ligand complexes predicted by molecular docking. Thus, it helps in boosting the virtual screening hit rates [31,49]. The accuracy of the method is limited by the lack of conformational entropy, missing effect of water molecules in the binding site and details in the method, such as dielectric constant, continuum-solvation method, and charges [50].…”