4QM0

Crystal structure of RORc in complex with a tertiary sulfonamide inverse agonist

Summary for 4QM0

• Entry DOI: 10.2210/pdb4qm0/pdb
• Descriptor: Nuclear receptor ROR-gamma, N-(2-methylpropyl)-N-({5-[4-(methylsulfonyl)phenyl]thiophen-2-yl}methyl)-1-phenylmethanesulfonamide, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: nuclear receptor ligand binding domain, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (Probable): P51449
• Total number of polymer chains: 2
• Total formula weight: 59194.67

Authors

Boenig, G.,Hymowitz, S.G.,Wang, W. (deposition date: 2014-06-14, release date: 2014-09-17, Last modification date: 2024-02-28)

Primary citation

Fauber, B.P.,Rene, O.,de Leon Boenig, G.,Burton, B.,Deng, Y.,Eidenschenk, C.,Everett, C.,Gobbi, A.,Hymowitz, S.G.,Johnson, A.R.,La, H.,Liimatta, M.,Lockey, P.,Norman, M.,Ouyang, W.,Wang, W.,Wong, H.
Reduction in lipophilicity improved the solubility, plasma-protein binding, and permeability of tertiary sulfonamide RORc inverse agonists.
Bioorg.Med.Chem.Lett., 24:3891-3897, 2014

PubMed Abstract: Using structure-based drug design principles, we identified opportunities to reduce the lipophilicity of our tertiary sulfonamide RORc inverse agonists. The new analogs possessed improved RORc cellular potencies with >77-fold selectivity for RORc over other nuclear receptors in our cell assay suite. The reduction in lipophilicity also led to an increased plasma-protein unbound fraction and improvements in cellular permeability and aqueous solubility.

PubMed: 25017032
DOI: 10.1016/j.bmcl.2014.06.048

Experimental method

X-RAY DIFFRACTION (2.195 Å)