| Sumario: | Density functional theory and a polarizable continuum model are used to (i) understand the affinity modulating mechanisms of the interaction between the metal-ion-dependent adhesion site (MIDAS) of a selected integrin, lymphocyte function-associated antigen-1 (LFA-1) and a ligand mimetic acetate molecule and to (ii) propose a new, promising family of inhibitors to block the interaction of the integrin with intercellular adhesion molecule-1 (ICAM-1). We quantify the effect of isolated factors, such as the metal coordination, the nature of the ligand or the cation present on the MIDAS, and the effect of the permittivity of the media. We show that the affinity for ligand decreases when metal coordination changes from the open conformation to the closed conformation. In addition, Mn and Zn showed to be good competitors for the octahedrically coordinated Mg and yielded excellent affinity values, whereas Ca in an octahedric environmet would decrease the affinity for the ligand. Our affinity studies of the open MIDAS showed that nitronate-derived or carboxylic acid-containing ligands may represent new promising scaffolds of future inhibitors. Finally, we show that affinities are always highly favored by low-dielectric environments, which explains the propensity of MIDAS motifs to be surrounded by hydrophobic residues in integrins and highlights the importance of including hydrophobic groups in the inhibitors.
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