Space, the final frontier...

With a great title like"Chemical Space Travel" I just couldn't pass up this early view article in ChemMedChem. Though I'm not sure that I totally buy into this as a method for discovering new drugs, it is an interesting concept nonetheless. Currently, it is estimated that there are 10²⁰ to 10²⁰⁰ "drugable" organic molecules. As it is impossible sift through all of these structures when searching for new lead compounds, knowing what region of chemical space to explore beforehand might be beneficial. Thus, researchers in the Reymond group at the University of Berne in Switzerland have developed a computer program that serves as a "spaceship" for chemical space travel; a point mutation generator serves as a "propulsion device," and a similarity score serves as a "compass." In simpler terms, starting from any molecular structure "A", this program first completes one of eight possible mutations on each atom/bond in the molecule: atom exchange, atom inversion, atom removal, atom addition, bond saturation, bond unsaturation, bond rearrangement, or aromatic ring addition. Then, the similarity between each mutant and the target compound "B" is measured. The 10 mutants that are most similar to the target "B" and 20 random mutant molecules are carried on for another round of mutation/selection. This continues on until one arrives at the target molecule "B," and along the way thousands of unique structures are generated.

One easy example is illustrated below: Starting from methane, 12 mutations produced cubane--but along the way 6638 unique compounds were generated, taking the 10 most similar to the target (in this case cubane) and 20 random compounds at each mutation step. All compounds that were unstable or not synthetically feasible were eliminated. In the same fashion, from cubane to methanol, there were only 7 steps necessary, and during the process almost 1000 new molecules were generated.

So how could this be used for drug discovery? Well, to do this, the authors investigated the chemical space between AMPA and CNQX (shown below); both are known to be agonists of the AMPA receptor, which is a glutamate receptor in the central nervous system. Using these two compounds, over 559,656 compounds were obtained after after 500 runs, which created this cool looking graph. Colors for the graphs are as follows: AMPA to CNQX, in green; CNQX to AMPA in blue, run-away compounds in gray, AMPA to CNQX mutant series in orange, CNQX to AMPA mutant series in pink, and in red are the best docking compounds--or in other words compounds that actually are predicted to bind into the active site of the AMPA receptor (this was determined through computational docking studies). If you haven't noticed, the novel inhibitor with the best predicted affinity for the AMPA receptor is a combination of an amino acid group from AMPA and an aromatic group originating from CNQX.

Image taken from ChemMedChem 2(5), 636.

So the next time you are looking for novel chemical inhibitors, why don't you just take a ride in a chemical spaceship...

Fair use?

I just read about this over on Chemistry Central. Basically, a graduate student blogger at the University of Michigan was threatened with legal action for using some copyrighted figures in her blog. Fortunately the matter has been resolved, but it still opens up the question: What is fair use?

Anyway, I'd almost prefer an email like that over this kind of unpleasantness. I guess I'm lucky that my boss is a nice guy.

Chemistry and......Sports???

Imagine my surprise this morning when I took a peek at the sports section of the daily newspaper here on campus:

The article doesn't have anything to do with chemistry (you can read it here if you are interested), but I still thought it was cool to see a periodic table on the front page of the sports section. All press is good press, right?

Aggravating Aggregation

Anyone interested in the field of high-throughput screening shouldn't miss this article which appeared online in the ASAP section of J. Med. Chem last week. Generally medicinal chemists can avoid false positives in screens by utilizing the well known Lipinski's Rule of Five or other computational methods that identify potential problematic molecules. Unfortunately, compounds that form colloidal aggregates are particularly troublesome; through sequestration of an enzyme from its substrate, these molecules usually appear to be good inhibitors (with IC50 values as low as 1 micromolar) with rather steep dose response curves. As aggregate-based inhibition is abrogated through the use of moderate concentrations of non-ionic detergents such as Triton X-100 (0.01 to 0.1%), Feng and coworkers developed an assay to test 70,563 compounds for detergent-sensitive inhibition. This screen has really opened my eyes to the prevalence of aggregators among screening hits. Astonishingly, of 1274 beta-lactamase inhibitors identified, 1204 were detergent sensitive, indicating an aggregation based mechanism of inhibition for 1.7% of the library! Anyone that has sorted through thousands or hundreds of initial hits will see the advantage of being able to identify or eliminate these artifacts from screens.

Discovering that a molecule is an aggregator is not a death sentence for its future use; as aggregation is concentration and condition dependent, molecules known to aggregate in one screen might not in a different setting. Additionally, several known drugs are aggregators at concentrations below 100 micromolar, including clotrimazole, nicardipine, delavirdine, and benzyl benzoate as pointed out by this 2003 article in J. Med. Chem.

Janus Disks

What exactly is a Janus disk? Well, with a quick internet search you can easily find several references to Janus, the Roman god of doorways, gates, and beginnings (hence the word January for the first month of the year), but a picture search is actually most revealing. Usually Janus is shown with two different faces that look in opposite directions; one represents the sun and the other symbolizes the moon. Interesting--but what does this have to do with chemistry??

Well after that brief review of Roman mythology, one can easily imagine that a Janus particle is composed of two fused hemispheres of different materials--similar to the bust of Janus pictured above. Depending on their actual shape, Janus particles are placed into three categories: spheres, disks and cylinders. Several potential applications of these two-sided particles have been envisioned. For instance, in solar cells two very different types of molecules (donors and acceptors) must work together and convert light into electron movement; thus, using Janus particles within light harvesting devices might increase solar cell efficiencies. One could also imagine a Janus-scaffold as a drug delivery system; half of the disk might target cancer cells, while the other end would deliver a cytotoxic drug.

Synthesis of Janus structures is a daunting task and only a few examples of non-spherical Janus particles exist in the literature; thus, when I came across this article in JACS today, it caught my attention. Researchers at the University of Bayreuth in Germany have recently succeeded in producing Janus disks utilizing a template-assisted synthesis. Polymers made of polystyrene-block-polybutadiene-block-poly(tert-butyl methacrylate) were self-assembled and then treated with either AIBN or S2Cl2 to crosslink the inner polybutadiene layer; this step preserves the orientation of the polystyrene and poly(tert-butyl methacrylate). Finally, after sonication the Janus disks are obtained in their final form; size of the disks is tunable and ranges from the micro- to nanometer scale. As Janus structures have also been proposed to have potential as surfactants, the effect of these Janus disks on the interfacial tension of liquid-liquid interfaces was studied as well. Compared to their un-crosslinked starting materials, the Janus disks have a remarkable ability to decrease interfacial tension, and therefore future technological applications might include the stabilization of emulsions or encapsulation of molecules.

Picture taken from http://dx.doi.org/10.1021/ja068153v

I want one...

A few days ago jungfreudlich posted pictures of his Element Collection. Very cool, don't you think? You can buy them online here, but probably not on a graduate student's salary :o)

Impact factors

Have you ever taken a few seconds to explore the impact factors of your favorite journals? If you've never done it before, I highly recommend taking a closer look at the ISI Web of Knowledge, especially the Journal Citation Reports (JCR). Whether or not you believe impact factors doesn't really matter--it's pretty interesting nonetheless.

For instance, the first article ever published with my name on it was in Organic Letters, which has an impact factor of 4.368 according to JCR. More recently, some of my work could be read in the international edition of Angewandte Chemie--impact factor 9.596. Does this mean I am slowly moving up the ladder of scientific respect? Well, there is actually a lot of debate about this subject, and some people believe that journal impact factors don't accurately represent the real importance of journals; would it be better to just use actual article citation numbers?

Before I move on, I think it is pretty important to understand how impact factor is calculated. Here is what goes into an impact factor calculation:



Using Angewandte Chemie International Edition as a real life example--in 2005 there were 11384 other articles citing articles from the year 2004, and 10620 other articles citing articles from the year 2003, for a grand total of 22004 citations. Divide this by the total number of articles published in 2003 and 2004 (2293) to get 9.596, the impact factor. Pretty simple, right? Well, the JCR reports a number of other interesting factors including the immediacy index (number of cites to "current" articles divided by number of current articles), journal cited half life (the median age of articles that are cited in the current year), and several graphs that condense some of this information.

Does the impact factor really measure the quality of a journal (or the importance of the articles published in the journal)? Well, it is true that some of the journals that I consider to be the best in the field have some of the highest impact factors. On the other hand, it's important to keep in mind that these numbers also reflect the latest trends in the literature. Availability of journals can be an issue, along with the amount of current interest and publication in a particular area.

Below is a condensed list of my favorite journals and their 2005 JCR impact factors: