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.
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.
authors.affiliation: Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China.
authors.forename: Shulin
authors.initials: S
authors.lastname: Zhuang
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zou
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Jiang
authors.forename: Xiang
authors.initials: X
authors.lastname: Mao
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.forename: Haichun
authors.initials: H
authors.lastname: Liu
authors.forename: Qingsen
authors.initials: Q
authors.lastname: Yu
mesh_terms: D002934:Cinnamates / Q000737:chemistry*; D008024:Ligands; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: C119726:2-fluoro-p-hydroxycinnamate; D002934:Cinnamates; D008024:Ligands; D008263:Macrophage Migration-Inhibitory Factors