Towards good correlation between fragment molecular orbital interaction energies and experimental IC₅₀ for ligand binding: A case study of p38 MAP kinase

We describe several procedures for the preprocessing of fragment molecular orbital (FMO) calculations on p38 mitogen-activated protein (MAP) kinase and discuss the influence of the procedures on the protein–ligand interaction energies represented by inter-fragment interaction energies (IFIEs). The correlation between the summation of IFIEs for a ligand and amino acid residues of protein (IFIE-sum) and experimental affinity values (IC₅₀) was poor when considered for the whole set of protein–ligand complexes. To improve the correlation for prediction of ligand binding affinity, we carefully classified data set by the ligand charge, the DFG-loop state (DFG-in/out loop), which is characteristic of kinase, and the scaffold of ligand. The correlation between IFIE-sums and the activity values was examined using the classified data set. As a result, it was confirmed that there was a selected data set that showed good correlation between IFIE-sum and activity value by appropriate classification. In addition, we found that the differences in protonation and hydrogen orientation caused by subtle differences in preprocessing led to a relatively large difference in IFIE values. Further, we also examined the effect of structure optimization with different force fields. It was confirmed that the difference in the force field had no significant effect on IFIE-sum. From the viewpoint of drug design using FMO calculations, various investigations on IFIE-sum in this research, such as those regarding several classifications of data set and the different procedures of structural preparation, would be expected to provide useful knowledge for improvement of prediction ability about the ligand binding affinity.