3FXV

Identification of an N-oxide pyridine GW4064 analogue as a potent FXR agonist

Summary for 3FXV

• Entry DOI: 10.2210/pdb3fxv/pdb
• Descriptor: NR1H4 protein, 12-meric peptide from Nuclear receptor coactivator 1, 6-(4-{[3-(3,5-dichloropyridin-4-yl)-5-(1-methylethyl)isoxazol-4-yl]methoxy}-2-methylphenyl)-1-methyl-1H-indole-3-carbox ylic acid, ... (4 entities in total)
• Functional Keywords: nuclear receptor, cholesterol, bile acid, dna-binding, metal-binding, nucleus, receptor, transcription, transcription regulation, zinc, zinc-finger, activator, acyltransferase, alternative splicing, chromosomal rearrangement, phosphoprotein, polymorphism, proto-oncogene, transferase, ubl conjugation, hormone receptor
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : Q15788
• Total number of polymer chains: 2
• Total formula weight: 29311.53

Authors

Feng, S.,Yang, M.,He, Y.,Chen, L.,Zhang, Z.,Wang, Z.,Hong, D.,Richter, H.,Benson, G.M.,Bleicher, K.,Grether, U.,Martin, R.,Plancher, J.-M.,Kuhn, B.,Rudolph, M.G. (deposition date: 2009-01-21, release date: 2009-04-14, Last modification date: 2024-04-03)

Primary citation

Feng, S.,Yang, M.,Zhang, Z.,Wang, Z.,Hong, D.,Richter, H.,Benson, G.M.,Bleicher, K.,Grether, U.,Martin, R.E.,Plancher, J.-M.,Kuhn, B.,Rudolph, M.G.,Chen, L.
Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist
Bioorg.Med.Chem.Lett., 19:2595-2598, 2009

PubMed Abstract: According to the docking studies and the analysis of a co-crystal structure of GW4064 with FXR, a series of 3-aryl heterocyclic isoxazole analogs were designed and synthesized. N-Oxide pyridine analog (7b) was identified as a promising FXR agonist with potent binding affinity and good efficacy, supporting our hypothesis that through an additional hydrogen bond interaction between the pyridine substituent of isoxazole analogs and Tyr373 and Ser336 of FXR, binding affinity and functional activity could be improved.

PubMed: 19328688
DOI: 10.1016/j.bmcl.2009.03.008

Experimental method

X-RAY DIFFRACTION (2.26 Å)