Drude SILCS-Nucleic: Harnessing Explicit Electronic Polarization in Targeting RNA and DNA for Drug Design.

The growing interest in nucleic acids as therapeutic targets has prompted the development of novel computational methods to facilitate drug discovery. In this study, we extend the Site Identification by Ligand Competitive Saturation (SILCS) methodology to characterize ligand-nucleic acid interactions using the Drude polarizable force field. We demonstrate the ability of the Drude force field to better model solute-nucleic acid interactions, resulting in improved identification of known binding sites and ligand binding favorability predictions across a diverse set of nucleic acid structures. This new workflow addresses limitations in previous SILCS studies by exploiting the enhanced sampling of solutes in the original SILCS-RNA workflow, accurately modeling the interactions of charged species, and improving solute sampling in minor groove binding sites. These results establish this Drude-based SILCS workflow as a valuable tool for structure-based drug design targeting nucleic acids and offer insights into solute preferences that can guide rational ligand design.