Project Poseidon

[cosmotroniks]

I hereby propose the following:

a project to utilize what free and commercially available cheminformatics software tools and even online server resources to analyze, from a neuropharmacological/pharmacodynamic standpoint, the series of chemicals synthesized and tested/tasted/evaluated by Dr. Alexander Shulgin, one of the greatest persons ever to live..

We share the same birthday, which has always been something special for me (albeit a different year, but the seventeenth day of June nevertheless).. it's interesting, because ever since I first heard about and then purchased and read his and Ann's two wonderful books, I feel that I can identify very much with the way he looks at the world and how things are 'put together'. Sorry - I don't really have a good set of words to articulate the way I feel about this 'connection' that I have with Dr. Shulgin. It's more than simple language can describe anyway. More like a "purpose connection".. even though we certainly have never met, I identify with some of what the good doc has expressed (a lot actually). And incidentally, I feel more and more every day that I was probably "born with an erlenmeyer flask in my hand".. my father owns a professional Carpet Cleaning and Water Damage Restoration company, and I can remember being like three or four years old, mixing his cleaning solvents and chemicals/surfactants together in the back of "The Warehouse" as I call it... and chemical reactions did indeed take place. I have no clue on earth what I synthesized, and didn't know back then either. But it was fun. Pure joy and bliss, as only a child can feel... and mixed with a bit of organic synthetic chemistry, albeit with a tad bit of ignorance as to what was actually happening, since I was less than five years old at the time.

I still vividly remember these beautiful neon pinkish-purple colored crystals that gradually precipitated out of the chancy solution/reaction mixture that I had prepared. One of the most beautiful sights I've seen. Like looking at a space nebula, but all sweet, fine and crystalline and shiny and glassy and right in front of my face... it was pure happiness. I love chemistry. It will always be my first and foremost passion, with music and automobiles/motoring coming in a close second and third, respectively.

But anyways, enough of/about me. Let's get on with the real stuff:

I wanna take all (and when I say all, I mean ALL of the compounds listed and written up in the second halves of PiHKAL and TiHKAL, and subject them to docking and pharmacokinetic/pharmacodynamic and even general chemical analysis through the modern magic of that wonderful scientific specialty called Computational Chemistry/Cheminformatics... I have tons and tons of resources and software on my machine that I can use for the purpose.

So here goes:

The first one (they won't necessarily be evaluated/analyzed in the same order in which they appear within the texts.. so bear with me. gonna pick and choose as I see fit, at least for now)... so here we go:

#1 analysis sub-project of the larger initiative I am proposing, called "Project Poseidon", is ALEPH, or 2,5-dimethoxy-4-methylthioamphetamine. The ALEPH series has always intrigued me because of its more abstract mental effects as described in PiHKAL (both Parts I and II of course).

Here's a 'couple initial results (bear with me; the molecular docking thing is gonna take a while to set up..)

 

[JamtasticX]

That's pretty cool, Pikal and Tikal would be much more informative if they had those, and I'm not an expert at chemistry so I like how you showed what each node was, helps to identify it better.

What are you using? I have ChemStudio 2008 but am just starting to figure out the basics.

 

[wungchow]

So what are you trying to do, exactly?

You take 1H-NMR spectra and energy-minimized conformations for various PIHKAL/TIHKAL compounds, and correlate them to subtle differences in psychoactive effects? I think it's a lot more complicated than that... that's an inquiry more suited to the study of biochemistry/biology than computational chemistry...

 

[Astavats]

What are you using?

Looks like ChemBioDraw.

 

[vecktor]

how about the project is renamed the poseidon adventure because it seems likely to capsize and sink without trace.

 

[MurphyClox]

Everything that I've seen so far is a predicted 1H-NMR (worth= next to nothing) and the calculated mass, both done with ChemDraw.

1. How are these going to assist with docking studies?

2. How do you plan to advance next? I'm right in the middle of getting the clue how to do dock molecules in protein structure, too, but can't see anything that resembles what I have learned recently.

3. Which software are you going to use for 2.?

4. Where do you get the 3D-structures of your targets from (5HT-receptors, DA-receptor, NE-receptor; reuptake-transporters of those transmitters, too; ...)? These are needed, otherwise you have nothing to dock into...


We shall talk again when these 4 simple questions were answered. "Poseidon" you say? Sounds indeed adventurous...


- Murphy

 

[sekio]

Most, if not all GPCRs (G protien coupled receptors) have unknown structures - and it just so happens that most of the receptors you would want to look into are GPCRs (CB1 and 2, 5-HT1 and 2, a- and B-adrenergic, etc)

 

[MurphyClox]

^That was what point 4. was aiming at.

Seriously, guys, please let cosmotroniks answer these 4 points. I am not making fun of him, but rather try to demonstrate the most urgent issues to be solved first.

And to answer 4., now that it has already been said: There are exactly two published 3D-structures of human GPCRs (to my best knowledge):

- the ß2-adrenergic receptor (see: Nature 2007, 450, p.383 or Science 2007, 318(5854), p.1258 )
- the adenosine A2A-receptor (see: Science 2008, 322(5995), p.1211)

All docking studies that aim at either the 5HTx-, DA-, NE- or any related receptor must begin with preparing an aligned model of those, using either rhodopsin as template or (better) one of the aformentioned publications. There are actually publications (co-authored by Nichols!) that demonstrate the possibility of preparing such a model, but in contrary to the actually measured crystal structures are the calculated ones not available online. (see the Brookhaven protein databank for the downloadable structures of the abovementioned receptors.

It is MUCH harder that it may look like at the first glance! Nonetheless: Good luck!


PEACE! - Murphy

 

[seep]

Your NMR machine is low on toner.

 

[cosmotroniks]

The NMR spectral analysis prediction has nothing whatsoever to do with what I am trying to accomplish here...

We're talking about molecular docking primarily.

I used ChemBioDraw Ultra 2010 to do the NMR spectral predictions. The only reason I posted those up is... well.. there isn't really a reason. I guess it just makes the identity of the substance clear from an analytical point of view.

No, what I'm really trying to accomplish here is docking analysis. I've got Autodock 4/MGL Tools, in addition to SYBYL-X.

What I plan to do is build three-dimensional models of the respective compounds and then tie that in with receptor protein models acquired through SwissModel.

SwissModel's really cool - you can provide a protein sequence and it builds a PDB model file for you. Totally automated. Plug in the data and go...

I'm in the process of getting things set up for docking simulation - bear with me.

 

[Hammilton]

You have no idea what you're talking about.

Yeah, it'll take a AA sequence and spit out a protein. Sort of. That protein is a flat, straight string of AA's. That's absolutely useless for docking. You need to find a closely related protein of known structure and base your model of the new protein on that. It's extremely difficult and takes a lot of time. There's a reason pHd's are awarded for this.

 

[Phener]

Distributed computing! Get all the bluelighters to have a screen saver which uses spare computing power to crunch through binding data! (like they do with aids/cancer drugs + SETI) :D

^yeah I know probably need a phd in computing to set that up, still I would SO be running that application rather than searching for ET.

 

[seep]

Distributed computing! Get all the bluelighters to have a screen saver which uses spare computing power to crunch through binding data! (like they do with aids/cancer drugs + SETI) :D

^yeah I know probably need a phd in computing to set that up, still I would SO be running that application rather than searching for ET.

Believe it or not, Bluelight's done this already.

Can't find the thread; it's not in this subforum. I think I contributed, but that was 3 laptops ago.

Edit: Here it is.
.