"Rules" and Binding

[Ham-milton]

I was wondering if anyone has a good explanation for what I'm about to ask.

For receptors for whom there is a 'rule' for binding, or even those that there isn't, how is it that some day we find some entirely different molecule that binds?

I'm thinking of fentanyl v. herkinorin and JWH-081 v. d-9-THC.

Is it that there are two general rules, one for amines, and another for terpenoids? Not even considering that peptides also bind to the same sites.

Especially for mu receptors, I guess. There you have a very well defined rule that when followed, may not be a sure thing, but it's as close as you can get. Then later we find out that something entirely different, ie: herkinorin (by way of salvinorin a's discovery).

The terpenoids also seem to be really potent, although that may just be luck, since with enough work, very potent amines are made.

So what gives?

 

[Jabberwocky]

well a rule is just our assessment of the behavior of these receptors with certain chemicals. Our knowledge of them is not exhaustive, as you point out, one chemical comes along a 'breaks the rule'. What happens then is we say to ourselves, "Oh, we did not have the right rule all along...here is the NEW (correct) rule."

 

[wungchow]

A lot of times the "rule-breaking" molecules will bind to different protein residues on the receptor, or simply have a different chemical structure but similar 3d geometry to the "rule-following" molecules.

For example, if you compare CP-55940 and THC, CP has an extra -OH group that hydrogen-bonds with another part of the receptor. Not all molecules fit into the same part of the 'lock'

 

[wungchow]

This journal article would be pretty revealing, for the CB1 receptor SAR...

http://pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/2000/43/i12/abs/jm991074s.html

Anyone have a subscription??

 

[Ängel1]

Well I hope I haven't terribly missunderstood the question but,
first, they're always on about orthosteric binding sites and allosteric alternative binding sites (oftne just modulatory) so that could explain why 2 entirely different molecules bind to one receptor i.e. entirely diferent binding sites.

But of course that was an easy stupid answer, I guess you mean 2 different molecules that do share the same binding site (i.e. they competitively displace a H3 marker in a binding assay). Well then I can just comment that

a) once you have a many dimentional pharmacophore of a binding site in a receptor you can more accurately predict bindings of very distinct molecules. the most modern molecular modelling packages offer a comprehensive comparison of many chemical descriptors. (do you have access to Sybyl packages by the way? or any other MM software that do the usual MEPs, gird potentials, CoMSA, etc, in order to fit molecules according to their similarities btw?).

b) of course one have to take into consideration that receptors are dynamic proteins that often have more that many thermodynamicaly favoured comformations (I just heard for example that Beta-adrenergic receptor2 has 2 distinct favored comformarions in an inactive state, as well as a basal activity 'leak' state).

 

[MurphyClox]

...once you have a many dimentional pharmacophore of a binding site in a receptor you can more accurately predict bindings of very distinct molecules. the most modern molecular modelling packages offer a comprehensive comparison of many chemical descriptors. (do you have access to Sybyl packages by the way? or any other MM software that do the usual MEPs, gird potentials, CoMSA, etc, in order to fit molecules according to their similarities btw?).

There were some talk very recently at the darker shade of the force (read: Blacklight) where some guys (including me ) compared potential opioids by overlaying the 3D-structures in Chem3D. The programm uses MM2. Results were already very convincing for a start...Maybe you'd like to contribute a bit to the discussion. Do you actually have access to Sybyl or other sophisticated modeling tools?!

Regards,

Murphy rocks around the Clox

 

[Ängel1]

Maybe you'd like to contribute a bit to the discussion. Do you actually have access to Sybyl or other sophisticated modeling tools?!

Sure I'd like to take a look, can you give us the link :D

I don't have access to Sybyl right now though, do you come up with 3d-QSAR equations with your opioids btw?

 

[Ham-milton]

you can join at blacklight.in

 

[Beenhead]

This journal article would be pretty revealing, for the CB1 receptor SAR...

http://pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/2000/43/i12/abs/jm991074s.html

Anyone have a subscription??

Im a member of the ACS and subscribe to a few journals but they charge extra fees to access online...

There is actually a article on a new article I just subscribed to the ACS journal of Pharmacognasy. It details a new Lysergamide looking compound isolated in a claviceps fungus. I cant get to it though...


Also there is an interesting article in one journal I get that talks about the structure of the protein Ubiquitin. There are many different partners that it forms a complex with. Now, in the normal fashion that proteins bind in a complex is through intereactions with the partner or the presence of some other factor that makes on conformation better suited at the given time than another. Ubiquitin constantly changes conformation all of the time, and if the right partner comes at the right time the complex forms.
There are many different ways in which substrates bind to their enzyme/protein. This was only found with fairly different techniques than usually employed like activity assays and the like. So Im sure there are many ways that a substrate can bind to an active site that we have not found yet!

 

[MurphyClox]

Sure I'd like to take a look, can you give us the link [1]

I don't have access to Sybyl right now though, do you come up with 3d-QSAR equations with your opioids btw?[2]

[1]Link was already provided by Hammilton

[2]What in particular do you mean/want? To summarize our (indeed very basic!) computational approaches: We pondered about opioid-activity of galanthamine, which is essentially known for its AcChE-inhibition. The molecules, morphine & galanthamine, were modeled in a 3D-programm (Chem3D 11, which is part of the famous ChemOffice package, since version 11: ChemBioOffice), energy minimized with MM2, refined with AM1 (which did not alter much the conformation calculated by MM2). The molecules were then overlayed to compare similarities.
I admit, this is a very basic approach but the program offers much more, which hasn't been evaluated yet by our members at the dark side of the force. I would welcome plp with some knowledge in computational chemistry A LOT! For example, in the case of galanthamine vs. morphine the structural similarity is awesome and even with such basic methods we were able to derive some first assumptions

Peace! Murphy

 

[MurphyClox]

There is actually a article on a new article I just subscribed to the ACS journal of Pharmacognasy. It details a new Lysergamide looking compound isolated in a claviceps fungus. I cant get to it though...[1]

Also there is an interesting article in one journal I get that talks about the structure of the protein Ubiquitin. There are many different partners that it forms a complex with. Now, in the normal fashion that proteins bind in a complex is through intereactions with the partner or the presence of some other factor that makes on conformation better suited at the given time than another. Ubiquitin constantly changes conformation all of the time, and if the right partner comes at the right time the complex forms. [2]

[1]Could you at least provide a name of the journal, volume and 1st page, plz? There is NO "Journal of Pharmacognosy", nor by ACS neither by anybody else. There was once an "International Journal of Pharmacognosy", which is now part of "Pharmaceutical Biology". But this journal again is published by Taylor & Francis, not ACS.

[2]This is called in biochemistry "induced fit", a theory not really new. Look here (if you have access):
"Application of a Theory of Enzyme Specificity to Protein Synthesis". Proc Natl Acad Sci U S A 1958, 44, p.98-104

 

[Beenhead]

The journal of Natural Products, the name eluded my at the time.
its a webrelease, so find it in the most recent web articles
Claviceps nigricans and Claviceps grohii: Their Alkaloids and Phylogenetic Placement
Im not sure if it is considered a Lysergamide, but LSA is in there... actually Ergocristam has been around for a while, I think the structure threw me, the article sounds interesting however.

The induced fit model is a little different than this, The whole protein changes constantly and not just the active site. Also the substrate has an effect on the changing of the conformation in the induced fit model. With Ubiquitin the protein is constantly changing shape, and it just happens that the substrate and protein arrive at the correct time during the correct conformational change.


D. E. KOSHLAND, JR. on the Induced Fit theory

"This set of postulates
has been called "the induced
fit" theory for brevity and to
emphasize that, while the idea
of a fit is retained from the
ENZYME 5 key-lock theory, the fit in this
case occurs only after the
Interaction of enzyme with the subtrate itself."