6LJS

Crystal structure of human FABP4 in complex with a novel inhibitor

Summary for 6LJS

• Entry DOI: 10.2210/pdb6ljs/pdb
• Descriptor: Fatty acid-binding protein, adipocyte, 2-[(2-phenylphenyl)amino]benzoic acid, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: fabp4, inhibitor, complex, lipid binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 17262.66

Authors

Su, H.X.,Zhang, X.L.,Li, M.J.,Xu, Y.C. (deposition date: 2019-12-17, release date: 2020-04-15, Last modification date: 2023-11-22)

Primary citation

Su, H.,Zou, Y.,Chen, G.,Dou, H.,Xie, H.,Yuan, X.,Zhang, X.,Zhang, N.,Li, M.,Xu, Y.
Exploration of Fragment Binding Poses Leading to Efficient Discovery of Highly Potent and Orally Effective Inhibitors of FABP4 for Anti-inflammation.
J.Med.Chem., 63:4090-4106, 2020

PubMed Abstract: Fatty-acid binding protein 4 (FABP4) is a promising therapeutic target for immunometabolic diseases, while its potential for systemic inflammatory response syndrome treatment has not been explored. Here, a series of 2-(phenylamino)benzoic acids as novel and potent FABP4 inhibitors are rationally designed based on an interesting fragment that adopts multiple binding poses within FABP4. A fusion of these binding poses leads to the design of compound with an ∼460-fold improvement in binding affinity compared to the initial fragment. A subsequent structure-aided optimization upon results in a promising lead () with the highest binding affinity among all the inhibitors, exerting a significant anti-inflammatory effect in cells and effectively attenuating a systemic inflammatory damage in mice. Our work therefore presents a good example of lead compound discovery derived from the multiple binding poses of a fragment and provides a candidate for development of drugs against inflammation-related diseases.

PubMed: 32202425
DOI: 10.1021/acs.jmedchem.9b02107

Experimental method

X-RAY DIFFRACTION (1.75 Å)