In Silico Analysis of Potential Stabilizer Binding Sites at Protein-RNA Interfaces.

Stabilizing rather than interfering with protein-protein interactions has emerged as a promising concept for designing drug molecules that can modulate protein-protein interactions. In addition to protein-protein interactions, protein-RNA interactions are involved in numerous cellular metabolic and regulatory processes, and it is desirable to stabilize these interactions, e.g., for potential pharmaceutical applications. In order to assess the potential that lies in protein-RNA interaction modulation by stabilizing drug molecules, we analyzed the binding interfaces of a large set of 87 protein-RNA complexes. Our in silico analysis revealed many interface cavities and potential binding sites that could fit drug-like compounds that can simultaneously interact with the protein and RNA. Through a systematic workflow combining interface pocket detection, molecular docking, and molecular mechanics coupled with the generalized Born surface area (MMGB/SA) calculations, we evaluated multiple pocket detection algorithms and identified key chemical features shared among in silico stabilizer candidates. The docking approach successfully reproduced portions of known experimental ligands and could be valuable for suggesting potential stabilizers of protein-RNA interactions.