Conformation-function relationship of vitamin D: conformational analysis predicts potential side-chain structure

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Structural Biology

Background:

• The vitamin D side chain's spatial regions (A, G, EA, EG) influence vitamin D receptor (VDR) affinity.
• Previous work established an order of VDR affinity based on these regions: EG < G < A < EA.

Purpose of the Study:

• To analyze the conformation-activity relationship of potent 1alpha,25-dihydroxyvitamin D3 analogues using the active space group concept.
• To correlate structural modifications in vitamin D analogues with their cell-differentiating potency.

Main Methods:

• Utilized the active space group concept to analyze ~40 potent 1alpha,25-dihydroxyvitamin D3 analogues.
• Calculated side-chain conformations using molecular mechanics and mapped them against defined spatial regions.
• Correlated cell-differentiating potency with the active space group concept.

Main Results:

• Potent analogues with natural C(20) configuration and modifications (22-oxa, 22-ene, 16-ene, 18-nor) had side chains in region F (in front of EA).
• The most potent 20-epi-22-oxa-24-homovitamin D analogues exhibited side chains in the L-EA region.
• Potency generally increased with side-chain location in the order A < F < EA < L-EA.

Conclusions:

• The active space group concept effectively explains the conformation-activity relationship for potent vitamin D analogues.
• Side-chain conformation relative to the EA region is a critical determinant of VDR affinity and biological activity.
• This framework aids in designing novel vitamin D analogues with enhanced VDR binding and potency.