Structure-activity relationship of nonsecosteroidal vitamin D receptor modulators

Area of Science:

• Pharmacology
• Structural Biology
• Medicinal Chemistry

Background:

• The vitamin D receptor (VDR) is a key drug target for bone disorders, cancer, autoimmune diseases, infections, and cardiovascular conditions.
• Approximately 100 nonsecosteroidal VDR modulators (VDRMs) have been developed to target the VDR.

Purpose of the Study:

• To analyze the structural basis of nonsecosteroidal VDRMs binding to the VDR.
• To understand the key interactions driving VDRM efficacy and potential therapeutic advantages.

Main Methods:

• X-ray crystallography was used to analyze the binding of nonsecosteroidal VDRMs to the VDR.
• Structure-activity relationships were investigated by comparing VDRM binding and activity to the natural ligand 1,25(OH)2D3.

Main Results:

• Nonsecosteroidal VDRMs bind to the VDR in a similar pose to 1,25(OH)2D3, with hydrogen bonds being crucial for binding.
• Hydrophobic and CH-π interactions are important for VDR binding, particularly in aromatic ligands.
• Modifications like replacing C-O-C with C-CH2-C linkages enhance transactivation activity, potentially due to entropic effects.
• Several VDRMs demonstrated superior therapeutic efficacy in experimental models of cancer and osteoporosis compared to 1,25(OH)2D3, with reduced hypercalcemia.

Conclusions:

• Structural analysis reveals key interactions governing VDRM binding and activity.
• VDRMs represent a promising class of therapeutics with improved efficacy and safety profiles for various diseases.
• Further development of VDRMs could lead to novel treatments for conditions like cancer and osteoporosis.