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Any chemists available?

Nools

Greenlighter
Joined
Mar 21, 2015
Messages
16
Location
United Kingdom
Hi, I'm Nools. I am currently an undergraduate student studying biology and I'm in my final year. I have been given the most bizarre assignment, for a biologist anyway, and I'm having real problems understanding it. My Professor is not being much help so I hoped I could ask some questions here or at least get some tips for where to start!

My brief is an impossible task, I think anyway. I have to alter the Digoxin molecule to try and improve it, the problem is I'm a biologist, not a chemist and I have no clue where to even start! Not only that but Digoxin has been around since the 1800s or before and I'm sure is already as perfect as it's going to get. We've been told to use molview and swissadme to alter the drug and I've read a few papers so far, so i understand that it works on a receptor outside the cell, the sodium ion transmembrane protein. It builds up calcium in the cell causing a positive inotropic effect. I understand that its therapeutic index is narrow and the chance for digoxin toxicity is high. I'd like to try to alter it to lower the toxicity but I'm sure if that could be done it would have been. I somehow have to change the molecule to get a slightly different response and justify my decisions.

Please does anyone have any advice they could give or know anything about Digoxin?

I hope this is posted in the right place, my apologies if not. Thanks in advance!

Nools :).
 

vecktor

Bluelight Crew
Joined
Jan 17, 2006
Messages
2,092
the main target is believed to be Na+/K+ ATPase which is an ion pump but there is clearly another pharmacologically important target. Changing the sugar linkage for another heterocycle gives things which are more potent at the ATPase but not more potent overall. Digitoxin is an allosteric inhibitor.

the dose response effect is biphasic, inhibition of a few of the pumps initially increasing overall pump speed of the rest of the pumps which is desirable and then at higher concentrations inhibiting the overall pump effect because it has knocked out too many of the pumps causing the ion levels not to recover before the next heartbeat, leading to slowing heart rate (bradycardia) then death.
So one trick to lowering toxicity and improving the therapeutic index is an analogue which has partial enzyme inhibition and a ceiling effect so no matter how much is used it cannot completely shut down the enzyme. maybe fast on fast off binding. Plenty of effort has been spent trying to do this over the years without much success in replacing digoxin, these efforts are not helped by digoxin being very cheap and once the dose is worked out correctly it is reasonably safe. Methyldigoxin has got some traction INN metildigoxin. swap the O methyl there for trifluoromethyl, or borrow some of the molecules out of this paper https://www.mdpi.com/1420-3049/5/1/51/htm run them through swiss adme or whatever software, insert your new results in your project, hand it in, collect your degree.

If you do come up with something hugely better in silico keep it completely quiet. Wait until after you graduate then contact Sanofi or Bayer and ask for a job, obviously don't mention you had the idea whilst still at university.

V
 
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