Nootropics DET/DMT synergy suggest a distinct "Psychedelic Modulator" subclass—structural & observational notes

[pantsoph]

It would be interesting to see if they stand out in the progression from methyl to propyl.

Also, just gonna be forthright with my bias here: I think in silico work is great for hypothesis generation, but it needs validation in actual biological systems.

I agree.

Classic Psychedelic Reference Compounds at 5-HT₂A

Compound	Amine–ASP155 (Å)	TRP Score	4-Sub Contacts	Key Contacts
DOM	2.86	0.246	ASN343 (3.40 Å), LEU229 (3.40 Å)	TYR370
DET	4.90	0.135	N/A	SER159, PHE340
DMT	4.59	0.178	N/A	SER159, PHE339/PHE340
DOET	4.27	0.293	SER242 (3.67 Å), PHE340 (3.77 Å)	ILE152 (2.70 Å)
2C-D	6.48	0.316	LEU229, SER239, ASN343	SER242-amine, PHE339/PHE340
2C-E	6.45	0.304	ASN343 (3.52 Å), PHE339 (3.99 Å)	SER242-amine, PHE339/PHE340
α-Ethyl-DOM	3.43	0.284	SER239 (3.41 Å), ASN343 (3.62 Å), LEU229 (3.68 Å)	TRP151 (3.80 Å)

Key Observations:
1. DOM is the structural reference standard
DOM maintains the tightest amine–ASP155 salt bridge (2.86 Å). The 4-methyl group packs cleanly against LEU229 and ASN343 without displacing the amine. The anchor is prioritized, and the TRP score remains moderate (0.246).
2. 2C-D and 2C-E lose the salt bridge entirely
Both compounds have the amine displaced > 6 Å from ASP155. This is a major structural shift:

• The amine instead H-bonds to SER242.
• ASP155 contacts the 2-methoxy group instead of the amine.
• 2C-E has a tighter ASP155–methoxy contact (3.32 Å) than 2C-D (3.46 Å) , suggesting the ethyl group pushes the ring further into the pocket and pulls the methoxy closer to ASP155.
• Both gain higher TRP scores (0.316 and 0.304) as the ring drops deeper into the orthosteric pocket.
• The 4-ethyl in 2C-E reaches further into the lipophilic pocket than the 4-methyl in 2C-D, touching PHE339 CZ at 3.99 Å.

3. DOET balances both anchor and lid
DOET maintains a moderate amine anchor (4.27 Å) while achieving a strong TRP score (0.293) and the best lid contact of the set (ILE152, 2.70 Å). The 4-ethyl contacts SER242 and PHE340.
4. α-Ethyl-DOM is the most balanced modulator candidate
α-Ethyl-DOM maintains a good amine anchor (3.43 Å) while achieving a strong TRP score (0.284). The α-ethyl reaches toward TRP151 (3.80 Å), distributing contacts across the deep pocket, the anchor, and the lid simultaneously.
5. DMT and DET maintain moderate anchors but low lid engagement
DMT and DET keep moderate amine anchors (4.59/4.90 Å) but have the lowest TRP scores (0.178/0.135). The tryptamine scaffold does not stack effectively with the pocket tryptophans.

Metrics:
Amine–ASP155 (Å): Distance between the ligand amine nitrogen and the closest ASP155 carboxylate oxygen. Lower = tighter salt bridge. < 3 Å = strong ionic H-bond; 3–5 Å = moderate; > 5 Å = amine displaced.
TRP Score: π-stacking between the ligand aromatic ring and all pocket tryptophans (TRP141, TRP151, TRP336, TRP367). Higher = more π-stacking.
4-Substituent Contacts: Receptor residues within 4 Å of the 4-position substituent carbons. Shows where the 4-sub packs—deep pocket, backbone, or lid.

 

[Skorpio]

I agree.

Classic Psychedelic Reference Compounds at 5-HT₂A

Compound	Amine-ASP155 (Å)	TRP Score	4-Sub Contacts	Key Contacts
DOM	2.86	0.246	ASN343 (3.40 Å), LEU229 (3.40 Å)	TYR370
DET	4.90	0.135	N/A	SER159, PHE340
DMT	4.59	0.178	N/A	SER159, PHE339/PHE340
DOET	4.27	0.293	SER242 (3.67 Å), PHE340 (3.77 Å)	ILE152 (2.70 Å)
2C-D	6.48	0.316	LEU229, SER239, ASN343	SER242-amine, PHE339/PHE340
2C-E	6.45	0.304	ASN343 (3.52 Å), PHE339 (3.99 Å)	SER242-amine, PHE339/PHE340
α-Ethyl-DOM	3.43	0.284	SER239 (3.41 Å), ASN343 (3.62 Å), LEU229 (3.68 Å)	TRP151 (3.80 Å)

DOM is the reference standard — tightest amine-ASP155 salt bridge (2.86 Å). The 4-methyl packs cleanly against LEU229 and ASN343 (both 3.40 Å) without displacing the amine. Anchor is the priority.
2C-D and 2C-E lose the salt bridge entirely — amine at 6.48/6.45 Å from ASP155. In exchange, they gain the highest TRP scores (0.316/0.304). The ring drops deeper into the orthosteric pocket. ASP155 contacts the 2-methoxy instead (3.46/3.32 Å). The 4-ethyl reaches further into the lipophilic pocket than 4-methyl, touching PHE339 CZ at 3.99 Å.
DOET balances both — moderate amine anchor (4.27 Å) with strong TRP score (0.293) and the best lid contact of the set (ILE152, 2.70 Å). The 4-ethyl contacts SER242 and PHE340.
α-Ethyl-DOM is the most balanced — maintains a good amine anchor (3.43 Å) while achieving a strong TRP score (0.284). The 4-methyl packs against SER239, ASN343, and LEU229. The α-ethyl reaches toward TRP151 (3.80 Å). This compound distributes contacts across the deep pocket, the anchor, and the lid simultaneously.
DMT and DET keep moderate anchors (4.59/4.90 Å) but the lowest TRP scores (0.178/0.135). The tryptamine scaffold can't stack effectively with the pocket tryptophans.

Metrics:
Amine-ASP155 (Å): Distance between the ligand amine nitrogen and the closest ASP155 carboxylate oxygen. Lower = tighter salt bridge. < 3 Å strong ionic H-bond, 3-5 Å moderate, > 5 Å amine displaced.
TRP Score: π-stacking between the ligand aromatic ring and all pocket tryptophans (TRP141, TRP151, TRP336, TRP367). Calculated as exp(−(d − d₀)/λ) × (90 − θ)/90 where d = ring centroid distance, θ = plane angle, d₀ = 7 Å, λ = 2 Å. Higher = more π-stacking.
4-Substituent Contacts: Receptor residues within 4 Å of the 4-position substituent carbons. Shows where the 4-sub packs — deep pocket, backbone, or lid.

Yeah like all of this ai construction really feels like you are running with a basic hypothesis and building so many other elements on top of it.

I worry that LLMs allow people to string together a web of plausible hypotheses, any one of which is interesting and worth testing, but as a whole they are as nimble and as long lived as a rat-king.

 

[pantsoph]

Yeah like all of this ai construction really feels like you are running with a basic hypothesis and building so many other elements on top of it.

I worry that LLMs allow people to string together a web of plausible hypotheses, any one of which is interesting and worth testing, but as a whole they are as nimble and as long lived as a rat-king.

I appreciate the concern about AI-generated webs. That's a real risk. But this framework is anchored in measurable docking data. For reference: (R)-EaM has an amine-to-ASP155 distance of 4.59 Å. This checks out when compared with my own personal experience with the compound when compared to my experience with other phenethylamines and reports I've read. 25E-NBOH has a salt bridge of 3.81.

 

[Skorpio]

I appreciate the concern about AI-generated webs. That's a real risk. But this framework is anchored in measurable docking data. For reference: (R)-EaM has an amine-to-ASP155 distance of 4.59 Å. This checks out when compared with my own personal experience with the compound.

I think we might have to simply agree to disagree on this one. I am not really party to the whole “drug experiences counting as evidence for chemical/biophysical phenomena” due to the messy subjectivity of the experience.

It feels like you are using that docking dataset to both create and validate your hypothesis which is a bit tautological.

 

[pantsoph]

I think we might have to simply agree to disagree on this one. I am not really party to the whole “drug experiences counting as evidence for chemical/biophysical phenomena” due to the messy subjectivity of the experience.

It feels like you are using that docking dataset to both create and validate your hypothesis which is a bit tautological.

i dont know what tautological means but sounds good

 

[Allylbenzene]

i dont know what tautological means but sounds good

Is English your first language?
I'm asking since if you're using some kind of translation software it could be helpful to know.

 

[pantsoph]

Is English your first language?
I'm asking since if you're using some kind of translation software it could be helpful to know.

yes english is my first language haha

 

[Skorpio]

i dont know what tautological means but sounds good

Circular reasoning. You are using data to make your hypothesis and then using that same data to test the hypothesis. It will be correct by definition.

It would be like me asking “if I stuck a screwdriver into an apple and then removed it, would the screwdriver fit into the hole left in the apple?”

 

[pantsoph]

Circular reasoning. You are using data to make your hypothesis and then using that same data to test the hypothesis. It will be correct by definition.

It would be like me asking “if I stuck a screwdriver into an apple and then removed it, would the screwdriver fit into the hole left in the apple?”

i made the hypothesis and then generated the data. The original Modulator post went up on August 10th. The docking table went up today (August 12th). The timeline is in the thread.

 

[Skorpio]

i made the hypothesis and then generated the data. The original Modulator post went up on August 10th. The docking table went up today (August 12th). The timeline is in the thread.

Forgive me, I thought all of this data was included in that paper you are working on.

Are docking programs still shit at handling mutagenesis? Because you could bolster your data by doing an alanine screen of key residues and analyzing the effect on your binding data. That would be a decent control.

 

[pantsoph]

Forgive me, I thought all of this data was included in that paper you are working on.

Are docking programs still shit at handling mutagenesis? Because you could bolster your data by doing an alanine screen of key residues and analyzing the effect on your binding data. That would be a decent control.

yeah i could mutate the 6wgt pdb in chimerax and compare thedocking results. which residues do you think would be best to inspect?

 

[Skorpio]

yeah i could mutate the 6wgt pdb in chimerax and compare thedocking results. which residues do you think would be best to inspect?

Honestly for rigor I would go with all of the Trps in the TRP score metric, Asp155, as well as any mentioned contact point you mention.


Does your docking system allow relaxation and equilibration of the mutated protein? This could be an issue if a switching a hydrophilic amino acid for an alanine (though I wouldn’t go for a glycine as that will mess up folding even more).

Another decent test to see how the system handles mutagenesis is throwing a bunch of bulk into the binding pocket (PHE usually) or removing the side chains (by mutating to Gly) and seeing how the binding is affected. If things still bind after these interventions than your binding software isn’t suited for mutagenesis.

 

[pantsoph]

Honestly for rigor I would go with all of the Trps in the TRP score metric, Asp155, as well as any mentioned contact point you mention.


Does your docking system allow relaxation and equilibration of the mutated protein? This could be an issue if a switching a hydrophilic amino acid for an alanine (though I wouldn’t go for a glycine as that will mess up folding even more).

Another decent test to see how the system handles mutagenesis is throwing a bunch of bulk into the binding pocket (PHE usually) or removing the side chains (by mutating to Gly) and seeing how the binding is affected. If things still bind after these interventions than your binding software isn’t suited for mutagenesis.

Good point. Do you know if there's published mutagenesis data for 5-HT₂A at ASP155 or the ECL2 tryptophans? If there's experimental work to compare against, it could help verify the docking results.