Structural insights into ligand binding features of dual FABP4/5 inhibitors by molecular dynamics simulations.

The fatty acid binding protein (FABP) 4 and 5 have been considered as potential targets for the treatment of metabolic diseases. A compensatory upregulation of FABP5 due to the gene ablation of FABP4 in adipocytes indicated the importance of dual FABP4/5 inhibitors. A few compounds have been discovered as dual FABP4/5 inhibitors. However, none exhibited equivalent inhibitory activity against both FABP4 and FABP5, and almost all compounds showed weaker inhibition against FABP5. To provide a better structural understanding for the design of potent dual FABP4/5 inhibitors, molecular dynamics simulations have been performed for 100 ns to disclose the ligand binding features in FABP4 and FABP5 using Amber14, respectively. Key residues were identified by analysis of close contact, hydrogen bond occupancy, binding free energy and alanine scanning mutagenesis. In addition, induced-fit effects have been observed upon ligand binding in the process of simulations. The shifted alkyl chain of ligand in FABP4 was significantly different from that in FABP5 due to the corresponding residues (Phe58 and Leu60). Thus, to avoid different steric effects made by these two residues, hydrophobic groups of suitable size should be taken into account. Besides, electrostatic and steric effects with Arg107 and Arg109 should be paid more attention to. The results will facilitate the rational design of dual FABP4/5 inhibitors.