6BNS

STRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN BOUND TETHERED WITH SRC co-activator peptide and Compound 25a AKA BICYCLIC HEXAFLUOROISOPROPYL 2 ALCOHOL SULFONAMIDES

Summary for 6BNS

• Entry DOI: 10.2210/pdb6bns/pdb
• Descriptor: Nuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1 Chimera, 2-[(2S)-4-[(4-fluorophenyl)sulfonyl]-7-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]-N-(2-hydroxy-2-methylpropyl)acetamide (3 entities in total)
• Functional Keywords: nuclear receptor, multiple binding modes, xenobiotic, promiscuous, ligand, nuclear hormone receptor, nuclear protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : Q15788
• Total number of polymer chains: 2
• Total formula weight: 81000.38

Authors

DHAR, T.G.,GONG, H.,WEINSTEIN, D.S.,LU, Z.,DUAN, J.J.W.,STACHURA, S.,HAQUE, L.,KARMAKAR, A.,HEMAGIRI, H.,RAUT, D.K.,GUPTA, A.K.,KHAN, J.A.,SACK, J.S.,CAMAC, D.M.,PUDZIANOWSKI, A.A.,WU, D.R.,YARDE, M.,SHEN, D.R.,BOROWSKI, V.,XIE, J.H.,SUN, H.,ARIENZO, C.D.,DABROS, M.,GALELLA, M.A.,WANG, F.,WEIGELT, C.A.,ZHAO, Q.,FOSTER, W.,SOMERVILLE, J.E.,SALTER-CID, L.M.,BARRISH, J.C.,CARTER, P.H. (deposition date: 2017-11-17, release date: 2017-12-20, Last modification date: 2024-03-13)

Primary citation

Gong, H.,Weinstein, D.S.,Lu, Z.,Duan, J.J.,Stachura, S.,Haque, L.,Karmakar, A.,Hemagiri, H.,Raut, D.K.,Gupta, A.K.,Khan, J.,Camac, D.,Sack, J.S.,Pudzianowski, A.,Wu, D.R.,Yarde, M.,Shen, D.R.,Borowski, V.,Xie, J.H.,Sun, H.,D'Arienzo, C.,Dabros, M.,Galella, M.A.,Wang, F.,Weigelt, C.A.,Zhao, Q.,Foster, W.,Somerville, J.E.,Salter-Cid, L.M.,Barrish, J.C.,Carter, P.H.,Dhar, T.G.M.
Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (ROR gamma /RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity.
Bioorg. Med. Chem. Lett., 28:85-93, 2018

PubMed Abstract: We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Y in the PXR assay for long term preclinical pharmacokinetic (PK) studies.

PubMed: 29233651
DOI: 10.1016/j.bmcl.2017.12.006

Experimental method

X-RAY DIFFRACTION (2.56 Å)