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.