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Computational chemist here, working at the moment on small molecule ligands in the context of drug discovery. The small molecule itself is the ligand. There is

by toddm 4y ago

Computational chemist here, working at the moment on small molecule ligands in the context of drug discovery. The small molecule itself is the ligand. There is interaction of the ligand with the binding site amino acids via hydrogen bonds to several locations on the ligand. Have a look at the RCSB PDB entry for 6EZO - ISRIB bound to eIF2B (the 3D view is https://www.rcsb.org/3d-view/6EZO https://www.rcsb.org/3d-view/6EZO), turn on Dynamic Bonds and click on the ligand. While this static shot does not reveal all the interactions (such as those that are longer-range, cation-pi, water-mediated, and so on) that one would see in a molecular dynamics simulation or by docking, it's very useful. Finally, when benzene is attached to something, it's a phenyl group; amphetamine is the ligand; and the functional group is amine, not amide.

derefr 4y ago
Thanks for that. Is there a term for a part of a molecule that takes part in “medium range” interactions — making the molecule electrostatically attracted toward/repulsed away from specific macromolecule binding sites, like is happening with the hydrogen bonds here — but which don’t then take part in any kind of redox or polymerization reaction once the molecule reaches close enough for such to take place? Because that’s what I meant here by trying to distinguish which part of these molecules is the ligand: which part is getting directly chemically reacted with / away (triggering the state change in the receptor), vs. the part being interacted with only indirectly in the sense of “a key that fits into a molecular lock vs. a key that doesn’t”. What I’ve been told is that the phenyl group in amphetamine isn’t reacted with / reacted away by a DA receptor binding site, but rather just gives it its binding affinity by being the right shape to fit into (and the right charge + mass to be attracted by) DAR and DATR binding sites without the indirect forces of the “walls” of these receptors repulsing it. Under this logic (if it’s sound, which you seem to be saying it’s not), a brominated phenyl group would really just be a bromide ion in direct reaction terms — it’d theoretically attach to any chloride channel. The phenyl group it’s riding on, would — along with the rest of the molecule — serve to ensure that the bromide ion only gets to come into contact with chloride channels inside receptors that allow a phenyl group inside them, rather than repulsing phenyl groups, or not being the right shape to accept phenyl groups. (This logic — again, if sound — would also suggest that chlorhexidine would have a similar nootropic effect if it could cross the blood-brain barrier.)
- toddm 4y ago
  Mid-range is hard to define, really. There are weaker electrostatic effects, and the pi-stacking and/or cation-pi effects are over longer ranges than h-bonds typically are. The whole molecule is the ligand: when you state you are "trying to distinguish which part of these molecules is the ligand," I again state that the whole thing is the ligand. The parts that bind to moieties in the active site vs. the parts that might not do so directly are equally important. In your example with amphetamine, I can assure you that the electron-rich conjugated aromatic ring is very important, even if you don't see hydrogen bonding. Remember, we are talking about overall steric and electrostatics here. If you want a bromide ion, just use a bromide salt: that directly gives you Br^{-1}. Swapping a single atom in a molecule can drastically change PK/PD properties, so caveat emptor. As for chlorhexidine, it's an antibacterial on the upper limit of breaking at least one of Lipinski's RO5, although that's not a showstopper. There is no guarantee at all that it would behave like a similar compound.

by toddm 4y ago

derefr 4y ago

Thanks for that. Is there a term for a part of a molecule that takes part in “medium range” interactions — making the molecule electrostatically attracted toward/repulsed away from specific macromolecule binding sites, like is happening with the hydrogen bonds here — but which don’t then take part in any kind of redox or polymerization reaction once the molecule reaches close enough for such to take place? Because that’s what I meant here by trying to distinguish which part of these molecules is the ligand: which part is getting directly chemically reacted with / away (triggering the state change in the receptor), vs. the part being interacted with only indirectly in the sense of “a key that fits into a molecular lock vs. a key that doesn’t”. What I’ve been told is that the phenyl group in amphetamine isn’t reacted with / reacted away by a DA receptor binding site, but rather just gives it its binding affinity by being the right shape to fit into (and the right charge + mass to be attracted by) DAR and DATR binding sites without the indirect forces of the “walls” of these receptors repulsing it. Under this logic (if it’s sound, which you seem to be saying it’s not), a brominated phenyl group would really just be a bromide ion in direct reaction terms — it’d theoretically attach to any chloride channel. The phenyl group it’s riding on, would — along with the rest of the molecule — serve to ensure that the bromide ion only gets to come into contact with chloride channels inside receptors that allow a phenyl group inside them, rather than repulsing phenyl groups, or not being the right shape to accept phenyl groups. (This logic — again, if sound — would also suggest that chlorhexidine would have a similar nootropic effect if it could cross the blood-brain barrier.)

toddm 4y ago
Mid-range is hard to define, really. There are weaker electrostatic effects, and the pi-stacking and/or cation-pi effects are over longer ranges than h-bonds typically are. The whole molecule is the ligand: when you state you are "trying to distinguish which part of these molecules is the ligand," I again state that the whole thing is the ligand. The parts that bind to moieties in the active site vs. the parts that might not do so directly are equally important. In your example with amphetamine, I can assure you that the electron-rich conjugated aromatic ring is very important, even if you don't see hydrogen bonding. Remember, we are talking about overall steric and electrostatics here. If you want a bromide ion, just use a bromide salt: that directly gives you Br^{-1}. Swapping a single atom in a molecule can drastically change PK/PD properties, so caveat emptor. As for chlorhexidine, it's an antibacterial on the upper limit of breaking at least one of Lipinski's RO5, although that's not a showstopper. There is no guarantee at all that it would behave like a similar compound.