Molecular Dynamics Exploration of Selectivity of Dual Inhibitors 5M7, 65X, and 65Z toward Fatty Acid Binding Proteins 4 and 5

Designing highly selective inhibitors of fatty acid binding proteins 4 and 5 (FABP4 and FABP5) is of importance for treatment of some diseases related with inflammation, metabolism, and tumor growth. In this study, molecular dynamics (MD) simulations combined with molecular mechanics generalized Born surface area (MM-GBSA) method were performed to probe binding selectivity of three inhibitors (5M7, 65X, and 65Z) to FABP4/FABP5 with K(i) values of 0.022/0.50 μM, 0.011/0.086 μM, and 0.016/0.12 μM, respectively. The results not only suggest that all inhibitors associate more tightly with FABP4 than FABP5, but also prove that the main forces driving the selective bindings of inhibitors to FABP4 and FABP5 stem from the difference in the van der Waals interactions and polar interactions of inhibitors with two proteins. Meanwhile, a residue-based free energy decomposition method was applied to reveal molecular basis that inhibitors selectively interact with individual residues of two different proteins. The calculated results show that the binding difference of inhibitors to the residues (Phe16, Phe19), (Ala33, Gly36), (Phe57, Leu60), (Ala75, Ala78), (Arg126, Arg129), and (Tyr128, Tyr131) in (FABP4, FABP5) drive the selectivity of inhibitors toward FABP4 and FABP5. This study will provide great help for further design of effective drugs to protect against a series of metabolic diseases, arteriosclerosis, and inflammation.