PDBsum entry 6ljs

Lipid binding protein

PDB id: 6ljs

Contents

Protein chain

136 a.a.

Ligands

EHR

EDO

Waters ×98

PDB id:

6ljs

Name:

Lipid binding protein

Title:

Crystal structure of human fabp4 in complex with a novel inhibitor

Structure:

Fatty acid-binding protein, adipocyte. Chain: a. Synonym: adipocyte lipid-binding protein,albp,adipocyte-type fatty acid-binding protein,afabp,fatty acid-binding protein 4. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fabp4. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.75Å R-factor: 0.185 R-free: 0.224

Authors:

H.X.Su,X.L.Zhang,M.J.Li,Y.C.Xu

Key ref:

H.Su et al. (2020). 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. PubMed id: 32202425 DOI: 10.1021/acs.jmedchem.9b02107

Date:

17-Dec-19 Release date: 15-Apr-20

Protein chain

P15090  (FABP4_HUMAN) -  Fatty acid-binding protein, adipocyte from Homo sapiens

Seq: 132 a.a.

Struc: 136 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/acs.jmedchem.9b02107

J Med Chem 63:4090-4106 (2020)

PubMed id: 32202425

Exploration of Fragment Binding Poses Leading to Efficient Discovery of Highly Potent and Orally Effective Inhibitors of FABP4 for Anti-inflammation.

H.Su, Y.Zou, G.Chen, H.Dou, H.Xie, X.Yuan, X.Zhang, N.Zhang, M.Li, Y.Xu.

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 3 with an ∼460-fold improvement in binding affinity compared to the initial fragment. A subsequent structure-aided optimization upon 3 results in a promising lead (17) 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.