A study of the interaction of cinnamate analogues with macrophage migration inhibitory factor (MIF) and P1G mutant from molecular dynamics simulations

As a critical mediator of the host immune and stress response, macrophage migration inhibitory factor (MIF) has the enzymatic activity and is involved in many MIF-related diseases. The site-directed mutagenesis showed that the mutation of Pro-1 to glycine has a substantial effect on the catalytic activity of MIF. To study the function of Pro-1 in catalytic reaction of MIF, the models of a series of cinnamate analogues complexed with MIF and its mutant P1G were studied using molecular docking and molecular dynamics simulations. The correlation coefficient between the calculated binding free energy with automated molecular docking and the experimental binding free energy was 0.83. For the cinnamate analogues, E-ligands have a N-H⋯O hydrogen bond with Pro-1 of MIF, while they have a N-H⋯O hydrogen bond formed between the Ile-64 of P1G. This binding mode difference is caused by the P1G mutation. The Z-ligands have no hydrogen bonds formed with Pro-1 of MIF or Ile-64 of P1G. No obvious binding mode difference was found between the binding of Z-ligands to MIF and P1G, which shows that this mutation does not have a significant affect on the binding of Z-ligands to P1G. This study will offer us a further understanding on the role of Pro-1 and will be of great significance to provide guide on structure-based drug design for MIF-related diseases.