The discovery of novel and selective fatty acid binding protein 4 inhibitors by virtual screening and biological evaluation |
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| Institution: | 1. Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510530, China;2. University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China;3. The Key Laboratory of Regenerative Biology, The Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;1. Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue, Tampa, FL 33620, USA;2. Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 E Fowler Ave, Tampa, FL, USA;1. Department of Pharmacy, “Drug Discovery” Laboratory, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy;2. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168 Messina, Italy;3. Department of Biomedical Sciences, Dentistry, and Morpho-functional Sciences, University of Messina, Via C. Valeria, 98125 Messina, Italy;4. Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy;5. Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55099 Mainz, Germany;1. Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford University, 300 Pasteur Drive, HH333, Stanford, CA 94305-5317, USA;2. Biomaterials and Advanced Drug Delivery Laboratory, Stanford University, Stanford, CA, USA |
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| Abstract: | 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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| Keywords: | Virtual screening FABP Molecular dynamics Mutagenesis Binding free energy |
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