This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.
Small Molecule Interactions
Small molecules are low molecular weight organic compounds, such as amino acids and water, that can interact with larger compounds, such a proteins at specific sites. These molecules are important in genetics because they can alter protein function as a whole, single out a specific domain of a protein, be temporally controlled and they are often used for drug discovery [1].
In order to easily find specific compounds that may pertain to the protein of interest, chemical libraries have been developed. These libraries can be very generalized, but often the most helpful are smaller, more specific. One common way to build a chemical library is to us a combinatorial scaffold approach where a key motif is the core of the library, and additional diversity elements are built around this core [2]. For example, a common target of drug companies is kinase inhibitors, so, in that case, a useful library would be small molecules that interact with kinase proteins.
There are two main ways to find which small molecules may interact with your protein of interest. The first is experimental screening, where the protein is expressed and purified in a screen to find small molecules that bind to it [1]. This can be very time consuming, expensive and may not lead to any effective ligand.
The second way to find a small molecule that may interact with the protein of interest, is structure based virtual screening. This involves obtaining an X-ray crystallography structure of the protein, and then a computer program is used to find small molecules predicted to bind to the protein [1]. An example of this is below.
In order to easily find specific compounds that may pertain to the protein of interest, chemical libraries have been developed. These libraries can be very generalized, but often the most helpful are smaller, more specific. One common way to build a chemical library is to us a combinatorial scaffold approach where a key motif is the core of the library, and additional diversity elements are built around this core [2]. For example, a common target of drug companies is kinase inhibitors, so, in that case, a useful library would be small molecules that interact with kinase proteins.
There are two main ways to find which small molecules may interact with your protein of interest. The first is experimental screening, where the protein is expressed and purified in a screen to find small molecules that bind to it [1]. This can be very time consuming, expensive and may not lead to any effective ligand.
The second way to find a small molecule that may interact with the protein of interest, is structure based virtual screening. This involves obtaining an X-ray crystallography structure of the protein, and then a computer program is used to find small molecules predicted to bind to the protein [1]. An example of this is below.
From YouTube 2012. Disco Docking - Computational Drug Design. Retrieved from:
http://www.youtube.com/watch?v=TTtrk0Ue-Cg
http://www.youtube.com/watch?v=TTtrk0Ue-Cg
FRMD7 Protein and Small Molecules
For this analysis, NCBI was used to search for any small molecules that interact with protein FRMD7. The results of this search yielded zero compounds, which means researchers have yet to find a small molecule that interacts with FRMD7 as a whole protein. When the FERM domain was searched independently, six results came back. This could be useful since the FERM C domain is the site of most mutations causing nystagmus, but none of the studies directly investigated neuron or nervous system development.
Analysis and Discussion
To date, there has yet to be an effective drug treatment to ease the symptoms of nystagmus. It would be beneficial for researchers to perform high-throughput assays to screen for any small molecule that would bind to FRMD7 and rescue any development. This would hopefully trick the motor neurons into a phenotype closer to wild type, without the risks and invasive nature of surgery. For more on this topic, please visit the Conclusions and Future Directions page of this website.
References
[1] Emre, N., Coleman, R., Ding, Sheng. (2007)
A chemical approach to stem cell biology. Current Opinion in Chemical Biology, 11, 252. Retrieved from http://gen677.weebly.com/uploads/8/6/5/7/865764/emre2007review.pdf
[2] Stockwell, B. R. (2004)
Exploring biology with small organic molecules. Nature, 432, 846. doi: 10.1038/nature03196
A chemical approach to stem cell biology. Current Opinion in Chemical Biology, 11, 252. Retrieved from http://gen677.weebly.com/uploads/8/6/5/7/865764/emre2007review.pdf
[2] Stockwell, B. R. (2004)
Exploring biology with small organic molecules. Nature, 432, 846. doi: 10.1038/nature03196
Site created by: Kristen Klimo
Last updated: 5/11/2012
University of Wisconsin-Madison
Last updated: 5/11/2012
University of Wisconsin-Madison