Pharmacology (R)EaM NBOH molecular dynamics at 5HT2a (6WGT)

[pantsoph]

It'll help to provide some context for your post.
It's a response to this comment on your original publication:

It's nice but if I see correctly there is no counter validation of the docking scores apart from the enantiomers? It just feels a bit lackluster to publish this. Docking softwares have so much wiggleroom. I don't see thermal annealing being done to optimize conformation either.

To address the reviewer's concern regarding docking flexibility and thermal stability, we performed explicit-solvent molecular dynamics on (R)-EaM and 25E-NBOH with simulated annealing (5 cycles, 100K→350K→310K) followed by production MD at 310K.

Over the course of the simulation, (R)-EaM maintained its docked binding pose with a mean heavy-atom RMSD of 1.35 Å and a maximum deviation of 1.97 Å, well within the commonly accepted stability threshold of 2.5 Å. The potential energy remained stable at approximately −6.73 × 10⁶ kJ/mol with no drift, and temperature was maintained at 310 ± 2 K throughout.

In contrast, 25E-NBOH exhibited significantly greater conformational flexibility (mean RMSD 2.56 Å, max 4.37 Å), sampling multiple orientations within the binding pocket and transiently losing key contacts. This demonstrates that the α-methyl group acts as a conformational restraint, stabilizing the binding pose and contributing to the slow dissociation kinetics predicted for (R)-EaM.

doi.org/10.26434/chemrxiv.15005650/v8

 

[Rectify]

That Alpha Methyl Kicked It Up A Notch, Eh?

 

[pantsoph]

That Alpha Methyl Kicked It Up A Notch, Eh?

Yeah, in a few ways. The α-methyl likely imparts slower dissociation kinetics, could mean roughly a 4x lower effective dose compared to 25E-NBOH, and based on the asp155 distance from the amine, it's more of a partial agonist than the full agonism you'd expect from 25E-NBOH. Longer duration of effects.

Id compare the difference between (R)EaM and 25-E-NBOH to be similar to the difference between DET and DMT; where the former is less intense, but can be useful as a modulator for enhancing the duration, potency, and resonance of other 5-ht2a agonists.