• Bluelight HOT THREADS
  • Let's Welcome Our NEW MEMBERS!

Flexible opioids (and indeed other classes)

clubcard

Bluelighter
Joined
Apr 12, 2013
Messages
1,443
I spent some time examining the conformation of opioids like Dimethylaminopivalophenone. I don't know if it's just my stupidity but can't this compounds equally conform to 2 different shapes? One of them overlays pethidine, the other does not. Similarly propiram with it's tertiary nitrogen is able to assume 2 different conformations. Do these compounds interconvene with the binding holding it into the active conformation?

I overlaid compounds like propiram with norbutorphanol (a rigid opioid) and it looks like 50% of the time, the aromatic and N: overlay perfectly and 50% of the time, they did not seem to overlay at all.

Maybe it's my stupidity but I did wonder if the weak opioids WERE weak because 50% of the atoms were not in the correct confirmation.
 

polymath

Bluelight Crew
Joined
Nov 4, 2010
Messages
1,797
Location
Northern Europe
If there's many conformations how the molecule can approach the receptor in "wrong" way and only one how it can approach it in the "right" way, then I think it's likely to have low affinity.
 

Nagelfar

Moderator: N&PD
Staff member
Joined
Nov 23, 2007
Messages
2,278
Location
Vancouver, Washington USA
It was my understanding that is it a lot more complex than this.

Molecules that need to take a certain conformation simply do when they approach the ligand site, the ionic bonding kind of 'nudges' them into that shape.

The boat or chair conformation of rings, or the cis or trans shape of the carbmethoxy, don't seem to change the affinity when only one specific shape has to be achieved to link up as imaging has shown. Perhaps even the ligands present are a major contributor to what conformation the molecule takes in vivo. (note esp. that in vivo & in vitro bonding can greatly differ for the same exact substance.)

In fact it was my thinking that being 'rigid' was almost always unfavorable because of the way in which ionic bonds act to anticipate the manner of form that has to be taken to attach.

This is a question that probably skims the line of the quantum architecture of molecules via their atoms, electron sharing, etc. A proper simulation of which would require computing power that even now is only being worked at.

I find it all very interesting.
 

sekio

Moderator: N&PD
Staff member
Joined
Sep 14, 2009
Messages
21,325
Location
streets of simcity
Do these compounds interconvene with the binding holding it into the active conformation?
Yes.

But this also means that no binding occurs unless the compound is currently in a conformation that allows it to bind the receptor, so generally speaking any flexible ligand will be a less effective agonist than a more rigid ligand that is "stuck" in a high affinity conformation.
 

S.J.B.

Administrator; Moderator: DitM
Staff member
Joined
Jan 22, 2011
Messages
5,050
Location
Canada
A rigid ligand will incur much less of an entropy penalty upon binding than a flexible one.
 

Nagelfar

Moderator: N&PD
Staff member
Joined
Nov 23, 2007
Messages
2,278
Location
Vancouver, Washington USA
A rigid ligand will incur much less of an entropy penalty upon binding than a flexible one.
I wonder if a flexible molecule might have the entire portion which interacts with the binding site be rigid, i.e. that much of it's structure exposed, but be flexible on the whole in a way that once it reaches the site, the protein or receptor has a flange or overhang where the freely moving part of the molecule gets stuck in a way which highly skewed the entropy of binding.

Probably a lot of drugs do this, but the specifics haven't become known due to the resolution of the site not being mapped out in detail, esp. w/ regard to the agonist in question.

Though if it were stopped from binding by it's "plasticity" and the same occurred, it might bind 'longer' but 'less often', perhaps even balancing out?
 

clubcard

Bluelighter
Joined
Apr 12, 2013
Messages
1,443
If there's many conformations how the molecule can approach the receptor in "wrong" way and only one how it can approach it in the "right" way, then I think it's likely to have low affinity.
There are 2 minimum energy conformations... one overlays M... the other not.
 
Top