9GYK

Vitamin D receptor in complex with Sila-f

This is a non-PDB format compatible entry.

Summary for 9GYK

• Entry DOI: 10.2210/pdb9gyk/pdb
• Descriptor: Vitamin D3 receptor A, Nuclear receptor coactivator 2, ACETATE ION, ... (5 entities in total)
• Functional Keywords: vdr, complex, agonist, transcription
• Biological source: Danio rerio (zebrafish); More
• Total number of polymer chains: 2
• Total formula weight: 36108.23

Authors

Rochel, N. (deposition date: 2024-10-02, release date: 2024-12-11, Last modification date: 2024-12-25)

Primary citation

Loureiro, J.,Seoane, S.,Sampaio-Dias, I.E.,Peluso-Iltis, C.,Guiberteau, T.,Brito, B.,Gregorio, C.,Perez-Fernandez, R.,Rochel, N.,Mourino, A.,Rodriguez-Borges, J.E.
First Sila-Vitamin D Analogues: Design, Synthesis, Structural Analysis and Biological Activity.
J.Med.Chem., 67:21505-21519, 2024

PubMed Abstract: The incorporation of silicon bioisosteres into pharmacological structures has been used as a strategy to improve the therapeutic potential of drugs. However, no secosteroidal silicon-containing VDR ligands have been developed. Here we report the design, synthesis, and biological activity of six analogues of the natural hormone 1,25-dihydroxyvitamin D3 (1,25D), which incorporate a silicon atom as a side chain-C25 isostere. The analogues were synthesized by the Wittig-Horner approach starting from Inhoffen-Lythgoe diol. The crystal structures of the complexes formed by the sila-analogues with the ligand binding domain of VDR revealed additional interactions of the sila-containing side chains that stabilize the VDR active conformation. These sila-analogues show similar VDR binding and transcriptional activity in comparison with the natural hormone 1,25D, but with significantly less hypercalcemic activity. The new analogues, when combined with chemotherapy, significantly decrease cell proliferation.

PubMed: 39610329
DOI: 10.1021/acs.jmedchem.4c02404

Experimental method

X-RAY DIFFRACTION (2.2 Å)