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  • Title: Some insights into the stereochemistry of inhibition of macrophage migration inhibitory factor with 2-fluoro-p-hydroxycinnamate and its analogues from molecular dynamics simulations.
    Author: Zhuang S, Zou J, Jiang Y, Mao X, Zhang B, Liu H, Yu Q.
    Journal: J Med Chem; 2005 Nov 17; 48(23):7208-14. PubMed ID: 16279779.
    Abstract:
    Macrophage migration inhibitory factor (MIF) exhibits tautomerase activity on phenylpyruvate and has E-stereochemistry preference. To investigate the binding modes of its competitive inhibitors and evaluate their binding affinities, molecular dynamics simulations together with MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) analysis were performed on MIF complexed with (E)-2-fluoro-p-hydroxycinnamate and five analogues. Pro-1 was discovered to form a bifurcated hydrogen bond between its protonated nitrogen and carboxylate oxygens of E-ligands and Tyr-36. No hydrogen bonds were found between Pro-1 and Z-ligands. This distinct binding characteristic of E- and Z-ligands with Pro-1 may be the main factor for the large difference in their binding affinities, which is consistent with the previous report that Pro-1 is essential for the catalytic activity of MIF. MM-PBSA analysis revealed that energy components including van der Waals, electrostatic, and hydrophobic interactions are in favor of binding, among which electrostatic interactions are predominant to the binding affinity difference.
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