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N&PD Moderators: Skorpio | thegreenhand
modeling the 5-HT 2a receptor
- Thread starter nirvus
- Start date
Jakeperson
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I would like to see that too.
yes mirtazapine. me three. i'll get it docked and rendered pronto. (well fairly pronto . . . it is the weekend in my hemisphere). thanks to all for support. and just to show love, i'll get that one and the ibogaine, which should also be interesting. went to ibogaine wiki page to get structure and just read up on it, lmao at the reference to hunter s. thompson's gag. hilarious.
skillet
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I did the conversion, took forever! I'll send you the pdb if you like.
Also, it would help if you put all the important residues in your renderings, and stick with a roughly consistent receptor orientation. The orientation in your last LSD pose is quite common, and similar to what I usually go for.
Again though, that pose looks wrong, the tertiary amine should be forming an ionic bond with Asp155, while the indolic nitrogen H-bonds to one of Ser 159, 239 or 242, I don't remember which off the top of my head.
thanks skillet, i would be very grateful if you could slip me that pdb. maybe i could get that lsd pose right! also, when using autodock programs, you don't just get one pose usually. you get a few, mostly the same, maybe a slightly different conformer or something, but lsd is known to have more than one binding mode in 5ht2a (if i understand correctly). this is one of the reasons for it's uncommon potency. i don't remember how many i got for lsd, but i do know i chose the one to render in pymol based on it's similarity to the image in a 2008 paper so it would look good to the department bigwigs, who are not necessarily lsd chemistry experts, right? lemme dig thru and see if i have a pose more to your liking ; )
also, you're absolutely right about consistency in rendering style. some of those shots are from when i was first learning to do this, so i was experimenting. now i know how to get the poses neatly composed and residue labels, etc. Any other ideas about this are welcome as constructive criticism. and i've been lurking for a WHILE, have seen some of your posts. you're one of the good ones.
when i put up ibogaine or mirtazapine (hopefully soon, but it's monday) those will be all new docking/rendering so check the technique and feedback is appreciated. all of you.
thanks,
nirvus
also, you're absolutely right about consistency in rendering style. some of those shots are from when i was first learning to do this, so i was experimenting. now i know how to get the poses neatly composed and residue labels, etc. Any other ideas about this are welcome as constructive criticism. and i've been lurking for a WHILE, have seen some of your posts. you're one of the good ones.
when i put up ibogaine or mirtazapine (hopefully soon, but it's monday) those will be all new docking/rendering so check the technique and feedback is appreciated. all of you.
thanks,
nirvus
skillet
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Your inbox is full, here's the file: http://www.filesonic.com/file/2304851801/5-ht2A_complete.pdb
Yeah there probably are several slightly different binding modes, but I'm pretty sure all of them will have the basic amine bonding to Asp155. I used to specify it as a constraint (really, you'd think the docking software could figure it out itself) or weird things happened! I still didn't manage to reproduce the ligand pose in the file though, and other ligands usually gave poses that didn't agree with experimental data. Hopefully you'll have more luck
Edit: There are a few recent active/agonist bound GPCR crystal structures that you can use as a template to possibly get a better model than the MD derived one:
3QAK - agonist bound adenosine A2A receptor
3P0G - nanobody stabilised active B2AR
2Y03 - agonist bound B1AR
2Y00 - partial agonist bound B1AR
Yeah there probably are several slightly different binding modes, but I'm pretty sure all of them will have the basic amine bonding to Asp155. I used to specify it as a constraint (really, you'd think the docking software could figure it out itself) or weird things happened! I still didn't manage to reproduce the ligand pose in the file though, and other ligands usually gave poses that didn't agree with experimental data. Hopefully you'll have more luck
Edit: There are a few recent active/agonist bound GPCR crystal structures that you can use as a template to possibly get a better model than the MD derived one:
3QAK - agonist bound adenosine A2A receptor
3P0G - nanobody stabilised active B2AR
2Y03 - agonist bound B1AR
2Y00 - partial agonist bound B1AR
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greatly appreciated. wow, look at those explicit water molecules all beggin' for molecular dynamics treatment. lovely bilayer gap there. <wipes drool from chin>. skillet you rock. and thanks for the pdb codes for the other gpcr's too. xmas in october.
about those binding modes: i was under the impression that it was Tyr 370 that was interfacing the tertiary amine and Asp 155 was somehow keeping the Tyr residue in the correct protonation state. they are very close in my model. will look into this and those other models when i get a minute.
BL: the gift that keeps giving
nirvus
about those binding modes: i was under the impression that it was Tyr 370 that was interfacing the tertiary amine and Asp 155 was somehow keeping the Tyr residue in the correct protonation state. they are very close in my model. will look into this and those other models when i get a minute.
BL: the gift that keeps giving
nirvus
skillet
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A carboxylic acid is way too weak a base to deprotonate a phenol. Asp155 will be >99% deprotonated at physiologic pH, and the ligand amine protonated to a similar extent, so that's likely to be the strongest bonding interaction. Tyr370 could H-bond with the ligand amine and Asp155 though, I think I sometimes saw a triangle of H-bonding during some of the MD I ran.
Desmond is free to download, and will do all the solvation, neutralisation, bilayer insertion and MD btw. (The intrahelical waters in the bilayer region you have to do manually, somehow, though. I think)
Desmond is free to download, and will do all the solvation, neutralisation, bilayer insertion and MD btw. (The intrahelical waters in the bilayer region you have to do manually, somehow, though. I think)
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ok so even though i hadn't slept much this weekend (i was busy, no stims), i still had to get into that model last night. removed water and G-protein and stuck it in Autodock Vina. was gonna do mirtazapine, but got funny results. i thought, hey it's in activated form so maybe an antogonist won't like binding to that. so i tried DOI. still got funny results, but then i realized i forgot to remove the bound NBOMe in the model. hehe, i really have done this b4 but it was late ; )
so yanked out the ligand and viola:
so yanked out the ligand and viola:
^note pi-stacking with phe340 and amine at asp155.
On this model, the tyr370 residue is further away from asp155, i have seen that same type of triangle formation in my homemade model. there are options for flexible residue positions with this one, will have to read more of paper to utilize that. desmond, you say? thx for tip.
decided to do mescaline next, want to play with it more b4 doing LSD. (wow that sounds incriminating don't it? lol)
anyway, here's mescaline in that active model:
On this model, the tyr370 residue is further away from asp155, i have seen that same type of triangle formation in my homemade model. there are options for flexible residue positions with this one, will have to read more of paper to utilize that. desmond, you say? thx for tip.
decided to do mescaline next, want to play with it more b4 doing LSD. (wow that sounds incriminating don't it? lol)
anyway, here's mescaline in that active model:
yes mirtazapine is definitely in the works. kinda busy at work. giving some prospective donors a demonstration at the university this week. also local buddhist meeting 2nite and don't forget to Occupy<your town>.
edit: the irony is not lost on me: chasing money for an institution while protesting institutions that chase money
edit: the irony is not lost on me: chasing money for an institution while protesting institutions that chase money
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quasi-degenerate
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- Jun 6, 2011
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Skillet- you are a gentleman and a scholar. I salute you for your fine PDB file!
I was thinking of putting together a "Research Workstation" virtual-machine with Docking, MD, Viz, etc. software already installed and properly configured, and perhaps a few scripts to download homology models, ligand-databases, and whatnot. I was thinking this would be a good way to get junior researchers (such as myself) up and running with less druge-work.
Do any of you have some recommendations for a platform and host OS for this virtual-machine? I was thinking VMWare / Mint Linux.
How about recommendations for software to install? I was thinking Chimera/VMD/NAMD/Autodock Vina.. I've worked with all of those but Vina.
Cheers!
I was thinking of putting together a "Research Workstation" virtual-machine with Docking, MD, Viz, etc. software already installed and properly configured, and perhaps a few scripts to download homology models, ligand-databases, and whatnot. I was thinking this would be a good way to get junior researchers (such as myself) up and running with less druge-work.
Do any of you have some recommendations for a platform and host OS for this virtual-machine? I was thinking VMWare / Mint Linux.
How about recommendations for software to install? I was thinking Chimera/VMD/NAMD/Autodock Vina.. I've worked with all of those but Vina.
Cheers!
ok, here's mirtazepine (Remeron). 5ht2a antagonist that is marketed as an antidepressant, and it is known to be at least as effective as SSRI's, but without the negative sexual side-effects (per wikipedia). Why is it not prescribed more often? Because it's generic, duh. And we all know big pharma will not give out pads/pens/coffee mugs/handjobs for out-of-patent but effective medications. </rant>
technical note: although i now have the 5ht2a active-state model (1,000,000 thanks skillet!), i decided to use the model i made myself since it is in all likelihood based the receptor's inactive config. why? because mirtazapine is an antagonist, i figure it probably prefers to bind to an inactive configuration. sound logical? input is welcome, and if anyone want me to, i could go back and do the docking with the active-state model. but i figure, maybe i should dock some strong agonists with that one. maybe psilocin next? trying to get some experience with the new model before doing the Big L(SD).
technical note: although i now have the 5ht2a active-state model (1,000,000 thanks skillet!), i decided to use the model i made myself since it is in all likelihood based the receptor's inactive config. why? because mirtazapine is an antagonist, i figure it probably prefers to bind to an inactive configuration. sound logical? input is welcome, and if anyone want me to, i could go back and do the docking with the active-state model. but i figure, maybe i should dock some strong agonists with that one. maybe psilocin next? trying to get some experience with the new model before doing the Big L(SD).