The discovery of novel and selective fatty acid binding protein 4 inhibitors by virtual screening and biological evaluation.
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±0.07μM, 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.
['Zhou|Yang|Y|', 'Nie|Tao|T|', 'Zhang|Yan|Y|', 'Song|Ming|M|', 'Li|Kuai|K|', 'Ding|Mengxiao|M|', 'Ding|Ke|K|', 'Wu|Donghai|D|', 'Xu|Yong|Y|']
D000818:Animals D002264:Carboxylic Acids D002460:Cell Line D055808:Drug Discovery D000074026:Fatty Acid Binding Protein 3 D050556:Fatty Acid-Binding Proteins D006860:Hydrogen Bonding D015850:Interleukin-6 D008024:Ligands D051379:Mice D062105:Molecular Docking Simulation D056004:Molecular Dynamics Simulation D016297:Mutagenesis, Site-Directed D054837:Quinolizidines D013329:Structure-Activity Relationship D014409:Tumor Necrosis Factor-alpha
Virtual screening Molecular dynamics Mutagenesis Binding free energy FABP