Friday 20 July 2007

In-silico drug design

This is the estrogen receptor. Women typically have a lot of the swimming around in their cytosol. Once estrogen binds, the complex moves to the DNA and transcription of the corresponding genes start.

In this picture there is only the ligand binding domain. They couldn't crystallise the whole protein because it was too flexible. Instead of showing different domains they chose to show the same domain three times. Alright: it's because of the crystallisation and XRD technique. The unit cell happens to have 3 unique molecules.

The small green things are the estrogens bound to their respective estrogen receptors. If you are trying to find a new drug that targets the receptor, these so called ligands and their binding sites are the most interesting part. The goal of in-silico drug design is screening a large library of molecules to find different molecules that also bind to a given receptor.

If you don't know what the structure of a protein looks like but you have the structure of similar proteins, you can go for homology modeling.

Once you have the structure of the binding site you try to dock ligands that will probably fit in your structure. First you have to find the right geometry of the ligand. After you have done that you have to score the docking, i.e. estimate the change in free energy of the docking process. This is rather difficult because there is no zero point energy to compare your docking pose with and because you have to include entropic effects.


Wavefunction said...

Not just the zero energy reference problem but also the fact that we simply don't understand and take into account all the interactions that the ligand has with the protein. Entropic effects are now gradually being included, most significantly by assigning penalties and rewards to water moelcules that are displaced. See the work of Rich Friesner and others (J. Med. Chem. 2005, PNAS 2007). But it's still a significant problem for sure. Also not included is the protein conformational entropy. But see
Nature Vol 448| 19 July 2007| doi:10.1038/nature05959

Brandon said...

There are several (many?) similar estrogen receptors, no? I think I remember from a pharm. class I took that different drugs target specific estrogen receptors. Do you know a ballpark figure of homw many types there are?

Felix said...

I'm afraid I don't know. this was just about a modelling example. I did not hear any more about the receptor

Malayang Mananaliksik said...

I suggest, you can explore those receptors. Your post is interesting because tackles not just its modelling aspect but its binding capabilities.

Are you familliar with Supramolecular Chemistry?

Felix said...

no, all I know about supramolecular chemistry is a little bit I read on wikipedia. and of course stuff I need for my project. maybe I'll write something about docking thermodynamics. because that's kind of interesting.