Probing In Silico the Benzimidazole Privileged Scaffold for the Development of Drug-like Anti-RSV Agents

Figure 1. Main examples of preclinical and clinical benzimidazole-based derivatives targeting RSV F protein.

Figure 2. In-house series of computational studies of benzimidazoles featuring anti-RSV ability. The R group represents halogen atoms, nitro group, or alkyl substituents.

Figure 3. Scheme of the applied computational protocol including structure-based studies and in silico predictive tools.

Figure 4. Superimposition of the X-ray complexes of the RSV F protein in presence of the two inhibitors RV521 (C atom in cyan; pdb code = 7KQD) [28] and JNJ-53718678 (C atom in magenta; pdb code = 5KWW) [27].

Figure 5. Molecular electrostatic properties at the RSV F protein surface surrounding the RV521 (C atom in cyan; pdb code = 7KQD) and JNJ-53718678 (C atom in magenta; pdb code = 5KWW) inhibitors (left side). The binding mode of TMC-353121 (C atom in cyan; pdb code = 5EA5) and BMS-433771 (C atom in yellow; pdb code = 5EA7) is also shown (right side).

Figure 6. Superimposition of the X-ray complexes of the RSV F protein in presence of the two inhibitors TMC-353121 (C atom in cyan; pdb code = 5EA5) [13] and BMS-433771 (C atom in yellow; pdb code = 5EA7) [13].

Figure 7. Potential energy (kcal/mol) and kinetic energy (kcal/mol) variation of the 5KWW complex as a function of time during MD_H (left side) and MD_E (right side) phases.

Figure 8. Potential energy (kcal/mol) and kinetic energy (kcal/mol) variation of the 5KWW complex as function of time during MD_P (200–1200 ps) phase.

Figure 9. Potential energy (kcal/mol) and kinetic energy (kcal/mol) variation of the 5KWW complex as function of time during MD_P (1200–2200 ps) phase.

Figure 10. Comparison of the X-ray data of JNJ-53718678 at the F protein surface (pdb code = 5KWW) with the positioning featured by the inhibitor based on MD simulations, MD_P. The related key contacts observed after 2 ns of MD_P are shown as tables. Distance values are reported in Å.

Figure 11. Comparison of the best scored JNJ-53718678 docking pose (red ligand) with respect to the same crystallized compound at the 5KWW PDB code (green ligand) by LeadIT molecular docking (left side) and by MOE Dock calculation (right side). RMSD values were evaluated by Pymol [35].

Figure 12. Comparison of the X-ray information about the JNJ-53718678 highly related analogues JNJ-49153390 (PDB code = 5EA4) [13], JNJ-36689282 (PDB code = 6VKD) [36], JNJ-36811054 (PDB code = 6VKC) [36], and RV521 (PDB code = 7KQD) [28] with the reference JNJ-53718678 (PDB code = 5KWW) [27]. The most recurrent conserved moieties and bioisostere substitutions are highlighted by light-blue circles and dot lines.