SPA-LN: a scoring function of ligand–nucleic acid interactions via optimizing both specificity and affinity

Nucleic acids have been widely recognized as potential targets in drug discovery and aptamer selection. Quantifying the interactions between small molecules and nucleic acids is critical to discover lead compounds and design novel aptamers. Scoring function is normally employed to quantify the interactions in structure-based virtual screening. However, the predictive power of nucleic acid-ligand scoring functions is still a challenge compared to other types of biomolecular recognition. With the rapid growth of experimentally determined nucleic acid-ligand complex structures, in this work, we develop a knowledge-based scoring function of nucleic acid-ligand interactions, namely SPA-LN. SPA-LN is optimized by maximizing both the affinity and specificity of native complex structures. The development strategy is different from those of previous nucleic acid-ligand scoring functions which focus on the affinity only in the optimization. The native conformation is stabilized while non-native conformations are destabilized by our optimization, making the funnel-like binding energy landscape more biased toward the native state. The performance of SPA-LN validates the development strategy and provides a relatively more accurate way to score the nucleic acid-ligand interactions.