8WDX

Crystal structure of human FABP4 complexed with C3

Summary for 8WDX

• Entry DOI: 10.2210/pdb8wdx/pdb
• Descriptor: Fatty acid-binding protein, adipocyte, 2-[(3-chloranyl-2-phenyl-phenyl)amino]-6-methyl-benzoic acid, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: lipid binding protein-inhibitor complex, lipid binding protein/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 17311.14

Authors

Xie, H.,Chen, G.F.,Xu, Y.C. (deposition date: 2023-09-16, release date: 2023-12-27)

Primary citation

Chen, G.,Xie, H.,You, M.,Liu, J.,Shao, Q.,Li, M.,Su, H.,Xu, Y.
Structure-based design of potent FABP4 inhibitors with high selectivity against FABP3.
Eur.J.Med.Chem., 264:115984-115984, 2023

PubMed Abstract: Fatty-acid binding protein 4 (FABP4) presents an attractive target for therapeutic intervention in metabolic and inflammatory diseases in recent years. However, highly similar three-dimensional structures and fatty acid binding ability of multiple FABP family members pose a significant challenge in design of FABP4-selective inhibitors. Particularly, inhibition of FABP3 raises safety concerns such as cardiac dysfunction and exercise intolerance. Here, we reported the discovery of new FABP4 inhibitors with high selectivity over FABP3 by exploiting the little structural difference in the ligand binding pockets of FABP4 and FABP3. On the basis of our previously reported FABP4 inhibitors with nanomolar potency, different substituents were further introduced to perfectly occupy two sub-pockets of FABP4 that are distinct from those of FABP3. Remarkably, a single methyl group introduction leads to the discovery of compound C3 that impressively exhibits a 601-fold selectivity over FABP3 when maintained nanomolar binding affinity for FABP4. Moreover, C3 also shows good metabolic stability and potent cellular anti-inflammatory activity, making it a promising inhibitor for further development. Therefore, the present study highlights the utility of the structure-based rational design strategy for seeking highly selective and potent inhibitors of FABP4 and the importance of identifying the appropriate subsite as well as substituent for gaining the desired selectivity.

PubMed: 38043490
DOI: 10.1016/j.ejmech.2023.115984

Experimental method

X-RAY DIFFRACTION (1.65 Å)