ITScore-NL: An Iterative Knowledge-Based Scoring Function for Nucleic Acid–Ligand Interactions

Nucleic acid-ligand complexes underlie numerous cellular processes, such as gene function expression and regulation, in which their three-dimensional structures are important to understand their functions and thus to develop therapeutic interventions. Given the high cost and technical difficulties in experimental methods, computational methods such as molecular docking have been actively used to investigate nucleic acid-ligand interactions in which an accurate scoring function is crucial. However, because of the limited number of experimental nucleic acid-ligand binding data and structures, the scoring function development for nucleic acid-ligand interactions falls far behind that for protein-protein and protein-ligand interactions. Here, based on our statistical mechanics-based iterative approach, we have developed an iterative knowledge-based scoring function for nucleic acid-ligand interactions, named as ITScore-NL, by explicitly including stacking and electrostatic potentials. Our ITScore-NL scoring function was extensively evaluated for its ability in the binding mode and binding affinity predictions on three diverse test sets and compared with state-of-the-art scoring functions. Overall, ITScore-NL obtained significantly better performance than the other 12 scoring functions and predicted near-native poses with rmsd ≤ 1.5 Å for 71.43% of the cases when the top three binding modes were considered and a good correlation of R = 0.64 in binding affinity prediction on the large test set of 77 nucleic acid-ligand complexes. These results suggested the accuracy of ITScore-NL and the necessity of explicitly including stacking and electrostatic potentials.