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Pharmacology Blog ( dopeisbeautiful.com ) : Unveiling the Beauty of Drug Action at Atomic Scale: An Exploration of Molecular Modeling

This thread contains discussion about a Pharmacology-related topic
G

GHBoners

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Aug 25, 2022
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Hello everyone,

I am thrilled to introduce my latest blog post from my site, "Dope is Beautiful". As a PhD in Molecular Modeling with a keen interest in consciousness studies, I delve into the fascinating world of molecular processes to illuminate how drugs interact with our nervous system at the atomic scale.

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You'll have the opportunity to understand how numerical models can be used to visualize the behavior of our nervous system at an atomic level. Not only does this provide a unique perspective, but it also sheds light on our understanding of biology and consciousness.

My first article is a dive into the binding site of the 5HT2B receptor coupled with its agonist LSD.

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You are invited to read the full article and immerse yourself in the captivating world of molecular modeling as it relates to the nervous system and consciousness. You can find the full blog post here: https://dopeisbeautiful.com/

I appreciate your thoughts, questions, and insights, so feel free to leave a comment on the blog post or reply to this thread. For those interested in staying up-to-date with the latest research and developments in this field, don't forget to follow my blog.

Looking forward to sharing this journey with you all!
 
I've been reading about kavain but the image doesn't let me see flumazinil or kavain clearly. It would also be nice to see a benzodiazepine with a pendant aromatic (i.e. a PAM) to see how the aromatic binds and to see how o-substitution of said ring further enhances affinity. Did you know that someone actually made and tested '2-nitro nitrazepam and it was as potent as flunitrazepam?

I looked at etifoxine and a few other to try to understand that pendent aromatic but it seems to be very specific to the benzodiazepines i.e. '2-chloro etifoxine was inactive and possibly even a NAM (if that is the term).

Truly lovely. My advice - write a book! I will buy a LOT.
 
By wanting to show you in more details the binding site of kavain, flumazinil and diazepam, I found that diazepam can actually fix on multiple sites in the GABA-A receptor (alpha1-beta2-gamma2 subtype), something that I didn't know. You have the allosteric binding site position I showed where my docking experiment put every kavalactones and where flumazinil is located in the PDB structure 6D6U where diazepam can bind. But on the PDB 6X3X, diazepam is also on a second binding site located at the membrane level.

On the PDB 6D6U structure, flumazenil seems to interact with its binding site mostly throught hydrophobic interaction with 3 aromatic residues. On the same site, diazepam interact with a shit lot more of residues. As you can see, I'm still fighting to find a great way to represent binding site clearly as it's not straightfoward! A fixed picture is great and stable, but to put everything on it is tricky. So I'd like to find way to make clear gifs to show the binding sites.

Gif of the flumazinil (green) and diazepam (magenta). Only amino acids that are interacting with the protein are shown. The dotted lines are the interactions.

bs_flu-1.gif
bs_diaz-1.gif

Edit: Ok this is dirty, but please bear with me I will progress on this point :D
After a few tests, it's seems there is some limit on the quality of the gif I can put here. Maybe I should go video on youtube. If you have tips about this, much appreciated! My principal aim is to bring clear (and beautiful if possible) structural information. We can even see our system in virtual reality now so it would be a shame that I can't find my way to present clean stuff here.

 
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Diazepam indeed binds to 4 subtypes but flumazinil is a non-selective antagonist. It simply has a much higher affinity than the PAMs in use and so reverses sedation. Etodamate is a fragment of flumazinil and that's a PAM so it's possible to work out which binding signals agonist or antagonist activity. With kavain, I think part overlays etodimate (a fragment of flumaznil) more or less and the other overlays the pendant aromatic.

I mentioned etifoxine because it's chiral and so is kavain. That might be of use when calculating active conformation.

But 'let yon bounty flow unstinting to thine own true pupils multifold and facet' to quote Cristopher Marlowe (if memory serves).
 
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