space final frontier

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 10^20 to 10^200 "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.