The number of known enzyme activators is minuscule compared to inhibitors. It may be that finding common features that help binding to allosteric binding sites is difficult due to the variety .
Are there any chemical, physical features that would pre-dispose a small molecule to be an activator rather than an inhibitor?
Dear Rajeev,
Each receptor has its different active site. Therefore, it is almost impossible to find a chemical entity (small molecule) that can activate all receptors.
To my knowledge, there is no physical or chemical features that can be considered to assist in activating receptors.
Hoping this will be helpful,
Rafik
It's much more common for researchers in the pharmaceutical industry to search for enzyme inhibitors, rather than activators, so there are an enormous number of known enzyme inhibitors originating from drug discovery programs. Inhibitors can be competitive, usually binding in the active site of an enzyme. Activators can't do that, so they have to bind in an allosteric site. Allosteric sites for small molecules have evolved to bind substances that are part of metabolic pathways, either upstream or downstream of the enzyme of which they are a part, as part of feedback mechanisms to control flux through the pathway.
Dear Adam,
I think that it is not necessary that the activator should bind to allosteric sites. It can bind to the active site itself. Moreover, some inhibitors act by binding to allosteric sites rather than to the active sites.
Rafik
I definitely agree that inhibitors can bind to allosteric sites. I think it must be very rare for an activator to bind to the active site, although perhaps it is a semantic issue. If you consider a co-substrate (such as a metal ion) or a cofactor (such as FAD, pyridoxal phosphate, or biotin), as an activator, then yes, an activator can, and must, bind in the active site.
Dear Adam and Rafik,
I was indeed not expecting a promiscuous activator. The difficulty of finding activators seems to be one factor in the imbalance between the no of known activators and inhibitors.
I was assuming for sake of discussion that most activators act at allosteric sites. Thus in my limited knowledge the sites might be smallish as compared to active sites, would be found MOSTLY on protein surfaces.
I would then expect some sort of geometric constraints between AA's in the site, the nature of AA's that would occur at protein surfaces as well as shape/ volume of the sites to be an important factor.
Correspondingly we can possibly look for really small binders with functional groups complementary to AA's with a propensity to occur on protein surfaces. This would only give us allosteric binders though and we may need further conformation information to differentiate activators from inhibitors.
If there's an upstream or downstream primary metabolite that binds to these sites for a given protein (Adam), maybe some sorta similarity measure to those could in itself help with this differentiation?
If you have a particular enzyme, or set of enzymes, in mind, then you can find out from the literature what compounds, if any, are known to be allosteric activators of it (them). One useful source of such information is the BRENDA database at brenda-enzymes.org.
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