Vitamin D: Structure‐function analyses and the design of analogs

Abstract

There is continuing and emerging new interest in the development of vitamin D analogs resulting from the recognition that analogs of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25-(OH)2D3] may be therapeutically useful. Side chain analogs of this steroid hormone are of particular interest because a family of lead structures have recently emerged for possible use in the treatment of certain types of cancers and skin diseases. Because of the chaotic array of side chain structures which exhibit useful therapeutic indices for these purposes, a more systematic approach towards developing intelligible structure-function information needs development. Accordingly, a method has been devised to analyze analogs as to their side chain topology based on identifying specific occupancy volumes through conformational analysis. Dot maps have been constructed as an indication of the volume in space which the side chain of 1 alpha,25-(OH)2-D3 or analogs is permitted to occupy. Volume exclusion analyses based on comparison of structural and biological data for 1 alpha,25-(OH)2-D3 and analogs are anticipated to lead to a more cogent model for drug design. A cautionary note on the limitations of this approach is discussed.

Three-dimensional model of the ligand binding domain of the nuclear receptor for 1?,25-dihydroxy-vitamin D3

“…The side chain is oriented in its 'northeasterly' or 2 o'clock orientation as defined by its global minimum energy (see Fig. 3B 'dot map' with line tracing of the side chain; [Okamura et al, 1992]). A: Four successive 90°rotations around the vertical axis of the VDR model present on the left side.…”

Analogs of Calcitriol

“…Following the 1991 report by Binderup about the increased overall activity of 20-epi-1,25(OH) 2 D 3 [21] it became clear that the orientation in space of the side chain plays an important role. Okamura developed a dot-map approach in order to visualize the portions in space that were accessible for the side chain, with focus on the 25-hydroxyl group [22,23]. This approach was further used by Yamada in a comprehensive structureefunction relationship study [24,25].…”

The role of mass spectrometry in vitamin D research

“…Thus, the flexible side chain in vitamin D analogs is believed to account for their varying degrees of biological activities compared to 1,25( OH),D,. Elfforts are currently underway to study the structure-function relationships of these vitamin D analogs (42), the results of which will aid in the design of other analogs that may be suitable for therapeutic use.…”