Structural and Energetic Analysis of 2‑Aminobenzimidazole Inhibitors in Complex with the Hepatitis C Virus IRES RNA Using Molecular Dynamics Simulations

Despite the many
biological functions of RNA, very few drugs have
been designed or found to target RNA. Here we report the results of
molecular dynamics (MD) simulations and binding energy analyses on
hepatitis C virus internal ribosome entry site (IRES) RNA in complex
with highly charged 2-aminobenzimidazole inhibitors. Initial coordinates
were taken from NMR and crystallography studies that had yielded different
binding modes. During MD simulations, the RNA–inhibitor complex
is stable in the crystal conformation but not in the NMR conformation.
Additionally, we found that existing and standard MD trajectory postprocessing
free energy methods, such as the MM-GBSA and MM-PBSA approaches available
in AMBER, seem unsuitable to properly rank the binding energies of
complexes between highly charged molecules. A better correlation with
the experimental data was found using a rather simple binding enthalpy
calculation based on the explicitly solvated potential energies. In
anticipation of further growth in the use of small molecules to target
RNA, we include results addressing the impact of charge assignment
on docking, the structural role of magnesium in the IRES–inhibitor
complex, the entropic contribution to binding energy, and simulations
of a plausible scaffold design for new inhibitors.