The discovery of novel and selective fatty acid binding protein 4 inhibitors by virtual screening and biological evaluation

• FABP4 is a promising drug target for treating inflammation-related diseases.
• Seven hits were obtained by using structure-based virtual screening.
• Similarity searches led to compounds with promising activity.
• An effective blockade of inflammatory response was validated in cell based assays.
• MD and mutagenesis studies validated important residues for ligand binding.

Adipocyte fatty acid binding protein (AFABP, FABP4) has been proven to be a potential therapeutic target for diabetes, atherosclerosis and inflammation-related diseases. In this study, a series of new scaffolds of small molecule inhibitors of FABP4 were identified by virtual screening and were validated by a bioassay. Fifty selected compounds were tested, which led to the discovery of seven hits. Structural similarity-based searches were then performed based on the hits and led to the identification of one high affinity compound 33b (Ki = 0.29 ± 0.07 μM, ΔTm = 8.5 °C). This compound’s effective blockade of inflammatory response was further validated by its ability to suppress pro-inflammatory cytokines induced by lipopolysaccharide (LPS) stimulation. Molecular dynamics simulation (MD) and mutagenesis studies validated key residues for its inhibitory potency and thus provide an important clue for the further development of drugs.

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