Some insights into the stereochemistry of inhibition of macrophage migration inhibitory factor with 2-fluoro-p-hydroxycinnamate and its analogues from molecular dynamics simulations.
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.
Zhuang
Shulin
S
Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China.
Zou
Jianwei
J
Jiang
Yongjun
Y
Mao
Xiang
X
Zhang
Bing
B
Liu
Haichun
H
Yu
Qingsen
Q
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
C119726:2-fluoro-p-hydroxycinnamate; D002934:Cinnamates; D008024:Ligands; D008263:Macrophage Migration-Inhibitory Factors