Novel fatty acid binding protein 4 (FABP4) inhibitors: virtual screening, synthesis and crystal structure determination

Haiyan Cai; Qiufeng Liu; Dingding Gao; Ting Wang; Tiantian Chen; Guirui Yan; Kaixian Chen; Yechun Xu; Heyao Wang; Yingxia Li; Weiliang Zhu

doi:10.1016/j.ejmech.2014.11.020

Novel fatty acid binding protein 4 (FABP4) inhibitors: virtual screening, synthesis and crystal structure determination

Eur J Med Chem. 2015 Jan 27:90:241-50. doi: 10.1016/j.ejmech.2014.11.020. Epub 2014 Nov 11.

Authors

Haiyan Cai¹, Qiufeng Liu², Dingding Gao³, Ting Wang⁴, Tiantian Chen⁴, Guirui Yan⁴, Kaixian Chen⁴, Yechun Xu⁵, Heyao Wang⁴, Yingxia Li³, Weiliang Zhu⁶

Affiliations

¹ Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University, School of Medicine, Shanghai, China.
² Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China.
³ School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
⁴ Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
⁵ Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: [email protected].
⁶ Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: [email protected].

PMID: 25461324
DOI: 10.1016/j.ejmech.2014.11.020

Abstract

Fatty acid binding protein 4 (FABP4) is a potential drug target for diabetes and atherosclerosis. For discovering new chemical entities as FABP4 inhibitors, structure-based virtual screening (VS) was performed, bioassay demonstrated that 16 of 251 tested compounds are FABP4 inhibitors, among which compound m1 are more active than endogenous ligand linoleic acid (LA). Based on the structure of m1, new derivatives were designed and prepared, leading to the discovery of two more potent inhibitors, compounds 9 and 10. To further explore the binding mechanisms of these new inhibitors, we determined the X-ray structures of the complexes of FABP4-9 and FABP4-10, which revealed similar binding conformations of the two compounds. Residue Ser53 and Arg126 formed direct hydrogen bonding with the ligands. We also found that 10 could significantly reduce the levels of lipolysis on mouse 3T3-L1 adipocytes. Taken together, in silico, in vitro and crystallographic data provide useful hints for future development of novel inhibitors against FABP4.

Keywords: Crystal structure; Diabetes; FABP4; Inhibitor; Virtual screening.

Publication types

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

MeSH terms

3T3-L1 Cells
Adipocytes / drug effects
Animals
Benzene Derivatives / chemical synthesis
Benzene Derivatives / chemistry
Benzene Derivatives / pharmacology*
Crystallography, X-Ray
Drug Discovery
Drug Evaluation, Preclinical
Fatty Acid-Binding Proteins / antagonists & inhibitors*
Lipolysis / drug effects
Mice
Models, Molecular
Molecular Structure
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*

Substances

Benzene Derivatives
FABP4 protein, human
Fatty Acid-Binding Proteins
Small Molecule Libraries
2,4,6-triisopropylbenzene