Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations

Abstract

In the last years, the development of small molecule antagonists of VLA-4 for the treatment of diseases, where cell tra±cking and activation are important, has increased considerably. Among them, the MK-0617 ligand has proven to be a highly potent and orally active 41 antagonist. However, the binding mode of this ligand in the integrin binding site remains unknown. Herein we report a thermodynamic analysis of the interaction between MK-0617 (and one of its isomers) and the VLA-4 protein using molecular docking and the free energy perturbation calculations, based on a comparative model of the 41 receptor. Initial complex coordinates were taken from molecular docking assays and submitted to alchemical transformations. Free energy of binding G values, derived from experimental IC50 values, were taken as a parameter for determining the most likely binding mode. In addition, molecular dynamics simulations of these ligands within the 41 binding site were carried out to elucidate the binding energy pro¯le and identify the most signi¯cant residues. Our results indicate that MK-0617 ¯ts within the binding site in a stretched conformation, pointing the carboxylate group towards the MIDAS ion. We observe that, despite the fact that the main contribution to the energetic binding process is due to the electrostatic ion contribution, the nonpolar contribution is not negligible. Additionally, a network of hydrogen bonds participate in stabilizing the ligand-receptor interaction.