Modeling the binding affinity of p38α MAP kinase inhibitors by partial least squares regression

The p38 mitogen-activated protein kinase is activated by environmental stress and cytokines and plays a role in transcriptional regulation and inflammatory responses. Factors influencing the activity and selectivity of the p38α mitogen-activated protein kinase inhibitors have been investigated in this paper by inspecting the binding orientation and the possible residue-inhibitor interactions in the binding site. The binding pattern of a set of 45 different inhibitors against p38α mitogen-activated protein kinase was studied through Molecular Dynamic Simulations of the protein-inhibitor complexes. Further, Partial Least Squares regression was used to develop a Quantitative Structure Activity Relationship model to predict the binding affinities of ligands. The selected model successfully predicted the test set with a Root Mean Square Error of Prediction of 1.36. The regression coefficients and the Variable Importance in Projection plots highlighted the residue-inhibitor interactions which exhibited the largest absolute effect on the ligand binding, such as the van der Waals interaction with LYS50, ILE81, ASP165; electrostatic interactions with SER29, LEU164; hydrogen bonds with MET106; and total energy interaction with SER29 and LEU83.