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

Yang Zhou; Tao Nie; Yan Zhang; Ming Song; Kuai Li; Mengxiao Ding; Ke Ding; Donghai Wu; Yong Xu

doi:10.1016/j.bmc.2016.07.022

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

Bioorg Med Chem. 2016 Sep 15;24(18):4310-4317. doi: 10.1016/j.bmc.2016.07.022. Epub 2016 Jul 12.

Authors

Yang Zhou¹, Tao Nie², Yan Zhang³, Ming Song³, Kuai Li², Mengxiao Ding², Ke Ding³, Donghai Wu⁴, Yong Xu⁵

Affiliations

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; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
² 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.
³ Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510530, China.
⁴ 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. Electronic address: wu_donghai@gibh.ac.cn.
⁵ Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510530, China. Electronic address: xu_yong@gibh.ac.cn.

PMID: 27460668
DOI: 10.1016/j.bmc.2016.07.022

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±0.07μM, 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.

Keywords: Binding free energy; FABP; Molecular dynamics; Mutagenesis; Virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carboxylic Acids / chemistry
Carboxylic Acids / pharmacology*
Cell Line
Drug Discovery
Fatty Acid Binding Protein 3
Fatty Acid-Binding Proteins / antagonists & inhibitors*
Fatty Acid-Binding Proteins / genetics
Hydrogen Bonding
Interleukin-6 / metabolism
Ligands
Mice
Molecular Docking Simulation
Molecular Dynamics Simulation
Mutagenesis, Site-Directed
Quinolizidines / chemistry
Quinolizidines / pharmacology*
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / metabolism

Substances

Carboxylic Acids
Fabp3 protein, mouse
Fabp4 protein, mouse
Fatty Acid Binding Protein 3
Fatty Acid-Binding Proteins
Interleukin-6
Ligands
Quinolizidines
Tumor Necrosis Factor-alpha
interleukin-6, mouse