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

Area of Science:

• Computational chemistry
• Drug discovery
• Molecular modeling

Background:

• Nucleic acids are increasingly recognized as crucial therapeutic targets.
• Developing effective computational methods is essential for accelerating drug discovery against these targets.
• Existing methods for characterizing ligand-nucleic acid interactions have limitations.

Purpose of the Study:

• To extend the Site Identification by Ligand Competitive Saturation (SILCS) methodology for improved characterization of ligand-nucleic acid interactions.
• To integrate the Drude polarizable force field into the SILCS workflow.
• To enhance the accuracy of predicting ligand binding sites and favorability for nucleic acid targets.

Main Methods:

• Utilized the Drude polarizable force field to model solute-nucleic acid interactions within the SILCS framework.
• Enhanced solute sampling, particularly in minor groove binding sites.
• Applied the methodology to a diverse set of nucleic acid structures.

Main Results:

• The Drude-based SILCS workflow demonstrated improved modeling of solute-nucleic acid interactions.
• Accurate identification of known nucleic acid binding sites was achieved.
• Enhanced prediction of ligand binding favorability across various nucleic acid targets.

Conclusions:

• The Drude-based SILCS workflow is a valuable tool for structure-based drug design targeting nucleic acids.
• This method overcomes limitations of previous SILCS studies, especially for charged species and minor groove interactions.
• The findings provide insights into solute preferences to guide rational ligand design for nucleic acid therapeutics.