Posts Tagged ‘Lutz Tietze’
Not simple analogues, but ligands for biological switches
by Phil on Mar 03 2009 (1151 Views)A while ago I blogged about a paper where a set of structures analogous to estrogen were made. Now a follow-up paper has appeared in Protein Engineering, Design and Selection. The aim was actually not to make simple analogues of estrogen, but to use the compounds to create specific receptor proteins.
Starting from the human estrogen receptor α, the authors employed directed evolution: they changed the residues in proximity of the ligand by mutagenesis, screened the resulting mutants, and selected the best receptor mutants for the next round. After the third round of directed evolution, they came up with an optimized mutant that bound to CV3320 with an EC50 of 55 nM, while the affinity to 17β-estradiol was reduced by a factor of 10 (4 nM).
While the authors admit that the selectivity over 17β-estradiol could still be improved, it still is a nice piece of work that demonstrates the power of directed evolution. This way, a protein receptor for a substrate that does not occur in nature can be made. Such a receptor can be used to make biological switches.
Estrogen analogues
by Phil on Mar 28 2008 (3551 Views)The authors of this paper (Chem. Eur. J. 2008, early view) have synthesized a series of new estrogen analogues where the B and C ring of estrone (1) and 17β-estradiol (2) are replaced with a simple alkyne spacer. The steric bulk of the omitted rings is replaced by suitable substitution of the two remaining “A” and “D” rings (phenols 3 and 4).
An overlay of the 3D structures of estrone (1, yellow) and 3 (white, R = 2-Cl, R’ = Me) shows a considerable offset between the corresponding carbonyl groups (O – O distance of 1.67 Å). I also wonder about the rotational flexibility of the linker – the “text-book”-property of steroids is their rigidity, but the new analogues can rotate about the triple bond.
The biological properties of these new compounds have not yet been measured. I wonder if they will be comparable to estrogens. If this radical structural simplification still yields bioactive compounds, this will be a remarkable achievement. On the other hand, flexibility always has an entropic cost when the molecules bind to their target, so I don’t expect the activities to be too high. Also, the new class of compounds is probably less selective than the original estrogens. But this is all speculation as long as the biology hasn’t been done.
