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 devel-opment 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 en-hanced 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.