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

Yinglei Sheng,Hirofumi Watanabe,Keiya Maruyama,Chiduru Watanabe,Yoshio Okiyama,Teruki Honma,Kaori Fukuzawa,Shigenori Tanaka

doi:10.1016/j.csbj.2018.10.003

Abstract

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.

Highlights

The fragment molecular orbital (FMO) method [1,2,3] allows for thequantum mechanical study of large biomolecules
The reason is that this protein has many entries of Xray crystal structures and experimental activity data; the 95 structures with IC50 data in the ChEMBL database [16] were available in the Protein Data Bank (PDB) [17]
Classification of proteins in terms of DFG-in/out-loop conformation First, we evaluated the correlation between the experimental IC50 values and the calculated inter-fragment interaction energies (IFIEs) for 78 complexes for Structures A, C′ and D', where these structures were optimized by the same force field and DFG-out conformations, respectively

Summary

Introduction

The fragment molecular orbital (FMO) method [1,2,3] allows for thequantum mechanical study of large biomolecules. It provides accurate protein–ligand interactions and their energetic components for each fragment pair, which is called the inter-fragment interaction energy (IFIE). We investigated the difference in IFIEs when different force fields based on molecular mechanics (MM) model were used to optimize the complexes.

Materials and computational methods

Correlation between pIC50 and ligand binding interaction energies

Influence of the complementation procedure for missing residues

Conclusion

2.55 Phe169