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modeling the 5-HT 2a receptor

p.s. someone i know personally who was intolerant of SSRI's side effects was briefly prescribed mirtazapine. she does not care much for serotonergics at all (hence intolerant of SSRI therapy) but noted that mirtazapine would quickly KILL a trip and allow sleep. it would cut right through a low-dose (5-10mg) 2c-e experience. i know this has been discussed elsewhere, but just my 2 cents. seems hospital emergency room/EMT's could maybe utilize a med with a pretty good safety profile to combat hallucinogen overdose. i think benzo's are weapon of choice currently ,which ain't bad, but this stuff would go right to the crux of the problem (at the 2a receptor). plus the strong antihistamine activity is fairly sedative. anyway. . .

edit: yay! 50 posts.
 
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tetrahydroharman: good idea. usually think of these in terms of their MAOI activity, but a quick search says yes, they bind to serotonin 2a receptor. so since i'm guessing it is an agonist, i used the active-state model from the 2011 paper (and converted to pdb format by skillet).

EDIT: MY FAULT!!!! oops how did mirtazapine get back in there??? oh geez, and that's not even the active model. i'm slippin. this is MIRTAZAPINE again:
tetrahydroharman.png
 
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okay for real this time, tetrahydroharman in the active 5ht2a model. sorry for the mixup, it's monday.
tetrahydroharman2.png
 
Perhaps you could try (R)-DOI, N-(2-hydroxybenzyl)-2C-I and its 2-methoxy-analog, TCB-2, and Br-DFLY. They are all full agonists.

Thank you for mirtazapine by the way!
 
quasi-degenerate said:
Skillet- you are a gentleman and a scholar. I salute you for your fine PDB file!
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Hehe, thanks! :D That might not be a bad idea to make a ready to go linux distro, might be better to include a variety of software though, so the user can try a bit of each and see what they prefer; though it means more work for you... I know I tried a lot of different stuff and dropped most of it before finding the programs that worked best for me. Vina is really easy to use, and quick, I just hated autodock tools that went with it, but maybe there's another way? And I don't know about running MD in a virtual machine, even docking can eat a ton of memory, depending on what you're doing and what software.

Nirvus, mirtazepine has it's own list of side-effects - weight gain and sedation to name two off the top of my head, so weather it's better or not I'm not sure. It's probably not worse.

Again, your new poses have Asp155 all on its lonesome, I don't think it's too presumtous to add a restraint between Asp155 and the most basic ligand nitrogen. A salt bridge is found in all the bound aminergic GPCR crystal structures AFAIK.

About the differences in the ligand binding site in active and inactive conformations, I think they're pretty small. I wouldn't really expect there to be too much difference whichever model you use for docking, effects from the inaccuracy of homology modelling are probably much greater. I think there's some discussion about it in the paper on the nanobody stabilised beta-2 AR structure.
 
SNR: yes i will do hydroxybenzyl-2ci. i think i may have already done NBOMe-2ci is that what you're asking? sorry correct me if i'm wrong, i'm having a busy week at work so forgive my hastiness. also i've done a rendering of tcb-2, but i guess you want a detail with residues labeled and all, a reasonable request. did i do the (S)-DOI enantiomer? i'll look into it. have you ever met an absent minded scientist? hehe. a lil' ego trippin' for sure, but i'm into a lot of different areas lately. i had time all summer (and for a few years when i was younger, before family life, etc) to do research in this area. now i'm s'posed to be doing conferences, hooking up with post-docs on projects, and lots of scholarly things but i find myself interested in my own family drama, and new social situations. (cryptic, i know but i can't exactly post pics of my personal life, suffice it to say i was a nerd, and now i'm loosing what few boundaries i had, i'm gonna go now and drink more champagne before i type any more in this parenthetical run-on sentence. stay in school.)
 
Published in January this year and stuffed with so much information that it instantly made me cum:

"G Protein- and Agonist-Bound Serotonin 5-HT2A Receptor Model Activated by Steered Molecular Dynamics Simulations"
J. Chem. Inf. Model. 2011, 51(2): 315–325

A 5-HT2A receptor model was constructed by homology modeling based on the β2-adrenergic receptor and the G protein-bound opsin crystal structures. The 5-HT2A receptor model was transferred into an active conformation by an agonist ligand and a Gαq peptide in four subsequent steered molecular dynamics (MD) simulations. The driving force for the transformation was the addition of several known intermolecular and receptor interhelical hydrogen bonds enforcing the necessary helical and rotameric movements. Subsquent MD simulations without constraints confirmed the stability of the activated receptor model as well as revealed new information about stabilizing residues and bonds. The active 5-HT2A receptor model was further validated by retrospective ligand screening of more than 9400 compounds, whereof 182 were known ligands. The results show that the model can be used in drug discovery for virtual screening and structure-based ligand design as well as in GPCR activation studies.
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^LOL, indeed! I always read your posts!

Must have overseen that one by tryp2fun.
 
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OK so i've been doing some of this modeling in 3D lately, and when i rendered the images, they came out as pairs. thought i'd see if anyone is interested in stereoscopic images like this, i know they're pretty hard to view w/ just 'eye-crossing' technique, but i've done it before. Maybe anaglyph 3D (red-blue) would render a single pic that you could see with the red-blue glasses. I'll check on that. point is, these docking poses make more sense in 3D.
domdm2t.png
 
^ that is DOM and DMT btw. guess which is which! and going back and trying 'cross-eyed' viewing of those pairs is damn near impossible for me, they're too busy. but if any of you have better luck or can think of some other way to post/view 3D images, lemme know. i'm just 3D spoiled/junky lately.

here's another 3D pair for haloperidol. and yes, i was going for creative, not scientifically sterile. I do some demo's to non-chem majors sometimes and i like it to look pretty. guess i'll chill with the 3D pairs, unless someone finds them useful. mainly i think it just looks too dumb sticking way off the page (ok my monitors not that hi-res). and i want to apologize in advance if i'm causing any headaches from eye-crossing. 8(
haloperidol2.png
 
I don't find it too hard to go cross-eyed and view the pictures you posted in a sort of 3D that's actually not that bad.
It looks really neat, and it makes it much easier to see which residues are behind of and in front of the ligand, as well as how far away/how close they are.
 
nirvus said:
OK so i've been doing some of this modeling in 3D lately, and when i rendered the images, they came out as pairs. thought i'd see if anyone is interested in stereoscopic images like this, i know they're pretty hard to view w/ just 'eye-crossing' technique, but i've done it before. Maybe anaglyph 3D (red-blue) would render a single pic that you could see with the red-blue glasses. I'll check on that. point is, these docking poses make more sense in 3D.
domdm2t.png
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Am I missing something here? I was under the impression that the indole amine ended up in the same location as the 2-methoxy group does of the PEA/DOx's? Not the same position as the alkylamine.

basement_shaman said:
I don't find it too hard to go cross-eyed and view the pictures you posted in a sort of 3D that's actually not that bad.
It looks really neat, and it makes it much easier to see which residues are behind of and in front of the ligand, as well as how far away/how close they are.
Click to expand...

Its cool isn't it. Its like magic eye. Very rad.
 
How about n,n dimethyl indole-propylamine?
And lucigenol?
And that weird structure that binds the n-nitrogen to the 4-carbon on the benzene in DMT
 
I tried lucigenol earlier, wasn't sure about the results

I'm working with another protein right now and doing site directed mutagenesis, and my opinion from the binding affinities of this very simple protein with docking the solved crystal structure versus the experimentally (radio experiments) obtained results is leading me to almost not even bother with docking anymore... There's a lot going on with a protein at 37C in solution and I think it's a mistake to rely too heavily on docking software.
 
Hi guys,
I have just spent much time searching for a useful link of 5ht2a pdb file, unsuccessfully. Could anyone of you please give me any advice where to find it or send me one? I would be very grateful. Thanks!
 
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