some small natural molecules have huge number of biological activities, such as Thymoquinone, Linalool, carvacrol "monoterpenes", quercetin, luteolin "Flavonoids"?
What makes them interactive with many key enzymes?
Dose the small size allows to these molecule to enter inside the enzyme pocket and then they interacts with other physiological molecules such as free amino acids by hydrogen bonds creating temporary active complex?
I am very astonished by the versatile activities of such molecules!!
Personally, I think that the most of the multipotency comes from the availability of protein active sites. Small molecules fit almost all proteins, exerting WEAK INTERACTION on them. I have highlighted "weak interaction" because we must note that, while small molecules have multiple activities, they are far less potent against a single protein compared with selective ligands. Take acetylcholinesterase (AChE) as an example... Despite that larger cyclic molecules (e.g. huperzine A, tacrine) strongly inhibit AChE, smaller ones such as some monoterpenoids (!) inhibit AChE, but in far larger dose. Evidence (see link below) has shown that hupyridone segment (the fragment having only 2 rings and 10 carbon atoms) can interact with AChE, but hupyridone itself is nontheless ineffective against AChE.
By the way, I think that, although it could be possible that small molecules temporariy form active complex with other molecules, it is unfavorible because of entropic reasons (those complexes are highly ordered species that are hard to form and would easily disintergrate upon disturbance). The more complex the complex, the more unfavorible.
http://www.rcsb.org/pdb/explore/explore.do?structureId=1H22
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