Cooperative Study Combining X-ray Crystal Structure Analysis and FMO Calculation: Interaction Analysis of FABP4 Inhibitors

X-ray crystal structural determination of FABP4 in complex with four inhibitors revealed the binding modes of the complexes, and the interactions between FABP4 and the inhibitors were analyzed. The detailed structure–activity relationship (SAR) could not be explained in terms of these crystal structural observations. Therefore, the interactions between FABP4 and the inhibitors were analyzed in more detail using fragment molecular orbital (FMO) method. This analysis revealed that the total interfragment interaction energies between FABP4 and each inhibitor correlated with the ranking of the Ki value for the four inhibitors. Furthermore, the interactions between each inhibitor and specific amino acid residues in FABP4 were identified. The oxygen atom of Lys58 in FABP4 was found to be very important for strong inhibitor–protein interactions. These results might provide useful information for the development of novel potent FABP4 inhibitors.