April 12, 2021, 03:23:56 AM
Forum Rules: Read This Before Posting


Topic: How come this drug works?  (Read 565 times)

0 Members and 1 Guest are viewing this topic.

Offline MathewConnors1999

  • Regular Member
  • ***
  • Posts: 13
  • Mole Snacks: +0/-0
How come this drug works?
« on: February 11, 2021, 08:54:14 AM »
How is it, in simple terms, that this drug is still permable when it does not fulfill neither lipinski's rule of five, nor fit within the Golden Triangle plot.
The this is the drug in question:(C24H26ClFN4O)

Offline AWK

  • Retired Staff
  • Sr. Member
  • *
  • Posts: 7984
  • Mole Snacks: +555/-93
  • Gender: Male
Re: How come this drug works?
« Reply #1 on: February 11, 2021, 09:24:25 AM »
What are the criteria of Lipinski's rule Sertindole does not fulfill?
AWK

Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 4600
  • Mole Snacks: +279/-19
Re: How come this drug works?
« Reply #2 on: February 11, 2021, 09:45:38 AM »
http://dx.doi.org/10.1016/j.ijpddr.2017.05.003
Lipinski and McKerrow coauthored a short article in 2017 that noted that some antiparasitics and fungicides fell outside the rule of five.  That particular point does not apply here, but IMO one has to be cautious not to throw the baby out with the bath more generally.  Obviously it is a worthwhile exercise to see whether or not sertindole falls within the rules and to ask why it is successful if it does not.
« Last Edit: February 11, 2021, 10:01:24 AM by Babcock_Hall »

Offline rolnor

  • Chemist
  • Sr. Member
  • *
  • Posts: 1306
  • Mole Snacks: +88/-5
Re: How come this drug works?
« Reply #3 on: February 11, 2021, 12:58:40 PM »
Many drugs does not follow these rules.

Offline MathewConnors1999

  • Regular Member
  • ***
  • Posts: 13
  • Mole Snacks: +0/-0
Re: How come this drug works?
« Reply #4 on: February 11, 2021, 01:13:53 PM »
What are the criteria of Lipinski's rule Sertindole does not fulfill?
Hello AWK
It says in my textbook that Lipinski's rules are more strict when talking about drugs where the brain is the target, whereas the first rule is that a drug should have a moleculeweight of under 400 g/mol as oppesed to the 500 g/mol limit set by lipinski´s generel rules. The molecule weight of the drug in question is 440.991 g/mol.
However I cannot see these more strict rules when I am reading about Lipinski's rules online. Perhaps it is not something used otherwhere than in my textbook?

But even if that is the case, the molecule still lays outside of the golden triangle plot. The drug's logD is caluclated as being 2.96 at pH 7.4.

http://dx.doi.org/10.1016/j.ijpddr.2017.05.003
Lipinski and McKerrow coauthored a short article in 2017 that noted that some antiparasitics and fungicides fell outside the rule of five.  That particular point does not apply here, but IMO one has to be cautious not to throw the baby out with the bath more generally.  Obviously it is a worthwhile exercise to see whether or not sertindole falls within the rules and to ask why it is successful if it does not.

Thank you for your answer. Interresting read indeed. Could you maybe point me to a clue as to why a drug could still be succesfuld even when not "being in line"

Another thing I am wondering, is that due to the logD being relatively high would indicate that the drug is largely nonpolar at pH 7.4. Another thing I found with the assistance of a Bjerrum Plot at pH 7.4 the drug is positively charghed when a hydrogen atom becomes H+ ion. How is it that these two pieces of information is 'crucial' to the drug's effectioness?
I ask because with this topic I constantly feel like I am floating just above understanding it, and I hope that I will be able to land. :)







Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 4600
  • Mole Snacks: +279/-19
Re: How come this drug works?
« Reply #5 on: February 11, 2021, 01:59:56 PM »
Another thing I am wondering, is that due to the logD being relatively high would indicate that the drug is largely nonpolar at pH 7.4. Another thing I found with the assistance of a Bjerrum Plot at pH 7.4 the drug is positively charghed when a hydrogen atom becomes H+ ion. How is it that these two pieces of information is 'crucial' to the drug's effectioness?
I ask because with this topic I constantly feel like I am floating just above understanding it, and I hope that I will be able to land. :)
Hydrogen atoms do not become H+ ions under ordinary circumstances.  In buffered solution (such as blood near pH 7.4) some chemical species may add a proton.  Which group on your molecule would that be?

With respect to your other question, I don't have any anti-parasitics in mind at the moment in this regard, but I will be on the lookout for one.
« Last Edit: February 11, 2021, 02:17:39 PM by Babcock_Hall »

Offline MathewConnors1999

  • Regular Member
  • ***
  • Posts: 13
  • Mole Snacks: +0/-0
Re: How come this drug works?
« Reply #6 on: February 11, 2021, 02:30:06 PM »
Another thing I am wondering, is that due to the logD being relatively high would indicate that the drug is largely nonpolar at pH 7.4. Another thing I found with the assistance of a Bjerrum Plot at pH 7.4 the drug is positively charghed when a hydrogen atom becomes H+ ion. How is it that these two pieces of information is 'crucial' to the drug's effectioness?
I ask because with this topic I constantly feel like I am floating just above understanding it, and I hope that I will be able to land. :)
Hydrogen atoms do not become H+ ions under ordinary circumstances.  In buffered solution (such as blood near pH 7.4) some chemical species may add a proton.  Which group on your molecule would that be?

With respect to your other question, I don't have any anti-parasitics in mind at the moment in this regard, but I will be on the lookout for one.

It would be on the tertiary amine group. I am not sure how to post pictures though. Any specific place the proton would come from?




Offline AWK

  • Retired Staff
  • Sr. Member
  • *
  • Posts: 7984
  • Mole Snacks: +555/-93
  • Gender: Male
Re: How come this drug works?
« Reply #7 on: February 11, 2021, 02:33:21 PM »
Sertindol was discovered before Lipiński published the first publication about his rules. This proves that these are just rules, not strict dependencies.
AWK

Offline Babcock_Hall

  • Chemist
  • Sr. Member
  • *
  • Posts: 4600
  • Mole Snacks: +279/-19
Re: How come this drug works?
« Reply #8 on: February 11, 2021, 02:39:13 PM »
It would be on the tertiary amine group. I am not sure how to post pictures though. Any specific place the proton would come from?
I agree that the tertiary amine group is almost certainly the site of protonation.  The buffering system in blood is based on carbon dioxide and bicarbonate.  The main buffering system in cells is thought to be phosphate.

Offline MathewConnors1999

  • Regular Member
  • ***
  • Posts: 13
  • Mole Snacks: +0/-0
Re: How come this drug works?
« Reply #9 on: February 11, 2021, 03:03:22 PM »
I agree that the tertiary amine group is almost certainly the site of protonation.  The buffering system in blood is based on carbon dioxide and bicarbonate.  The main buffering system in cells is thought to be phosphate.
This is really great! What effect has it that the molecule is positively charged in blood-pH?

Offline rolnor

  • Chemist
  • Sr. Member
  • *
  • Posts: 1306
  • Mole Snacks: +88/-5
Re: How come this drug works?
« Reply #10 on: February 11, 2021, 04:21:04 PM »
Protonation is a equilibrium, when the molecule is protonated its more watersoluble but when it crosses the blood-brain barrier its non-protonated. I dont know what happens when it binds to the receptor, is there a acidic amino-acid residue forming a ionic bond?

Offline MathewConnors1999

  • Regular Member
  • ***
  • Posts: 13
  • Mole Snacks: +0/-0
Re: How come this drug works?
« Reply #11 on: February 12, 2021, 01:13:32 AM »
Protonation is a equilibrium, when the molecule is protonated its more watersoluble but when it crosses the blood-brain barrier its non-protonated. I dont know what happens when it binds to the receptor, is there a acidic amino-acid residue forming a ionic bond?
Oh this makes sense, thank you.
With regards to what happens when it binds to the receptor, I am not quite sure yet. I will have to look into that a bit more.

Offline kriggy

  • Chemist
  • Sr. Member
  • *
  • Posts: 1447
  • Mole Snacks: +125/-16
Re: How come this drug works?
« Reply #12 on: February 15, 2021, 09:08:22 AM »
Sertindol was discovered before Lipiński published the first publication about his rules. This proves that these are just rules, not strict dependencies.
:spinup:
This

Also reading the original paper:
The rule of  5’  states  that:  poor  absorption  or  permeation  are more likely when there are more than 5 H-bond donors , Log  P  is  over  5  (or  MLogP  is  over  4.15), there  are  more  than  10  H-bond  acceptors  (expressed  as  the  sum  of  Ns  and  Os).

So its not like if you dont follow the strict rules the compound is unusable. Basically, what they did is they took bunch of compounds and set up the rules in a way that 90% of the used drugs at that time followed those rules.

Sponsored Links