8FB1

Experimental Data Snapshot

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

(2023) ACS Med Chem Lett 14: 191-198

PubMed Abstract:
Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound 14 demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers.

Organizational Affiliation

Medicine Design, Pfizer Inc., Cambridge, Massachusetts 02139, United States.

Macromolecule Content

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Nuclear receptor ROR-gamma	A, B	262	Homo sapiens	Mutation(s): 2 Gene Names: RORC, NR1F3, RORG, RZRG
UniProt & NIH Common Fund Data Resources
Find proteins for P51449 (Homo sapiens) Explore P51449 Go to UniProtKB: P51449
PHAROS: P51449 GTEx: ENSG00000143365
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P51449
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
XNR (Subject of Investigation/LOI) Query on XNR Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain F [auth B] MOL2 format, chain C [auth A] MOL2 format, chain F [auth B] mmCIF format, chain C [auth A] mmCIF format, chain F [auth B]	C [auth A], F [auth B]	N-(3-{[(3S)-4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl]methyl}-5-fluoro-2-methylphenyl)-4-fluorobenzene-1-sulfonamide C₂₅ H₃₁ F₂ N₃ O₃ S BARSGQAUTAPATR-KRWDZBQOSA-N		Interactions Focus chain C [auth A] Focus chain F [auth B] Interactions & Density Focus chain C [auth A] Focus chain F [auth B]
4Y5 Query on 4Y5 Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain G [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain G [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain G [auth B]	D [auth A], E [auth A], G [auth B]	4-{1-[2-chloro-6-(trifluoromethyl)benzoyl]-4-fluoro-1H-indazol-3-yl}-3-fluorobenzoic acid C₂₂ H₁₀ Cl F₅ N₂ O₃ PFVOSXMQCIFOSO-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain G [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain G [auth B]