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Hydrogen Bond Donor-Acceptor rules
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mjszabo

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Link to postPosted: Thu Jan 17, 2008 8:59 amPost subject: Hydrogen Bond Donor-Acceptor rules Reply with quote

Could you please describe what is the exact rule for counting Hydrogen Bond Donors and Acceptors in Chemaxon applications? Which atoms/groups are involved in the rules?

Thank you in advance,

Miklos
Jozsi
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Link to postPosted: Fri Jan 18, 2008 10:59 amPost subject: Reply with quote

Hi,


Acceptor atoms have to have a lone-pair electron.
A donor atom is connected with at least one H atom.

Additional useful details are given by Kubinyi. For example in these two references:
http://www.beilstein-institut.de/bozen2004/proceedings/Kubinyi/Kubinyi.htm
http://www.kubinyi.de/dd-18.pdf

Basically we accepted Kubinyi's results in our implementation.


Donor and Acceptor counts depend on the pH ( pKa ). This type of calculation was also implemented in our java package.

Cheers,
Jozsi
mjszabo

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Link to postPosted: Thu Mar 19, 2009 1:00 pmPost subject: Does tiophene sulphur is an acceptor? Reply with quote

Hi,
According to Kubinyi's investigation, an
oxygen atom is not an H-bond acceptor
in a furan ring. However, the sulphure atom is counted as an acceptor in a thiophene ring. Is this
correct?


To my understanding the same rule should be concerned
to an oxygen or sulphur connected to a sp2 or aromatic carbon.

Is there any way to customize the donor-acceptor
rules in Chemaxon?

Thank you,

Miklos
Jozsi
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Link to postPosted: Mon Mar 23, 2009 8:21 amPost subject: Reply with quote

Hi,

Quote:
Is this correct?

No, this is not correct. Sulphur is a weaker acceptor than oxygen. And since oxygen is not acceptor in furan ring   this is why sulphur can not act as an acceptor in thiophene ring.

We will fix this contradiction.


Quote:
Is there any way to customize the donor-acceptor

rules in Chemaxon?


  This type of user's interface is not available. We are going to develop such kind of interface soon.




Jozsi
moses

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Link to postPosted: Tue Aug 25, 2009 5:30 amPost subject: H-bond donor/acceptor algorithm and the Rule of 5 Reply with quote

Jozsi wrote:
Hi,


Acceptor atoms have to have a lone-pair electron.
A donor atom is connected with at least one H atom.

Additional useful details are given by Kubinyi. For example in these two references:
http://www.beilstein-institut.de/bozen2004/proceedings/Kubinyi/Kubinyi.htm
http://www.kubinyi.de/dd-18.pdf

Basically we accepted Kubinyi's results in our implementation.


Donor and Acceptor counts depend on the pH ( pKa ). This type of calculation was also implemented in our java package.

Cheers,
Jozsi

Hi Jozsi,

Is this still the algorithm that ChemAxon uses? Also, it might be good to note somewhere that this method is not the one Lipinski uses in the Rule of 5:

"There are more than 5 H-bond donors (expressed as the sum of OHs and NHs);
The MWT is over 500;
The 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);"

Best regards,

Moses

Jozsi
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Link to postPosted: Tue Aug 25, 2009 12:12 pmPost subject: Reply with quote

Hi,

 

1.

I described in the above part how donors and acceptors are defined in Marvin. I think they are defined correctly in Marvin. Don't you think so?

 

 2.

Lipinski rule of 5 requires only a subset of potential donor and acceptor centers. Only "Oxygen" and "Nitrogen" included in this subset.

Did you find any bug or problem with the Lipinski rule of 5 implemented by us?

 

Jozsi

Zsolt
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Link to postPosted: Tue Aug 25, 2009 12:48 pmPost subject: Re: H-bond donor/acceptor algorithm and the Rule of 5 Reply with quote

moses wrote:

Is this still the algorithm that ChemAxon uses? Also, it might be good to note somewhere that this method is not the one Lipinski uses in the Rule of 5:

"There are more than 5 H-bond donors (expressed as the sum of OHs and NHs);
The MWT is over 500;
The 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);"

Best regards,

Moses

Hi Moses,

I think the quoted definition of Lipinski's Rule of 5 is not correct.

Lipinski's rule says that, in general, an orally active drug has no more than one violation of the following criteria:


  • Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)
  • Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)
  • A molecular weight under 500 daltons
  • An octanol-water partition coefficient log P of less than 5

The corresponding Chemical Terms expression is:

(mass() <= 500) && (logP() <= 5) && ((disjointMatchCount('N[H]') + disjointMatchCount('O[H]')) <= 5) && ((atomCount('7') + atomCount('8')) <= 10)

I hope this helps.

Zsolt

moses

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Link to postPosted: Tue Aug 25, 2009 7:37 pmPost subject: Reply with quote

Jozsi wrote:

Hi,

 

> 1. I described in the above part how donors and acceptors are defined in Marvin. I think they are defined correctly in Marvin. Don't you think so?

 Hi Jozsi:

I'm actually not a computational chemist, so I'm not qualified to say whether it's right, but I'm sure you guys are on top of it. My question was simply whether you still use that algorithm, so that we can forward it to customers when they ask us what algorithm is used.

As far as whether the rule of 5 is implemented correctly, you don't have an explicit chemical terms expression for it (i.e. ruleOfFive() or something like that), so there's nothing wrong there. My comment was only that you might want to note somewhere that donorCount() and acceptorCount() are not for use with the Lipinski Rule of 5, because he used a simplified donor/acceptor count algorithm, and if you don't use that algorithm the statistics on which the Rule of 5 is based don't come out the same.

Also, I've noticed that in Instant JChem the rule of 5 provided as a "favorite chemical terms expresion" when adding a new chemical terms column does use donorCount() and acceptorCount().

So, just to follow up with a clearer question: Do you still use that algorithm, so we can tell our customers that's the algorithm used for donorCount() and acceptorCount()?

Moses

moses

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Link to postPosted: Tue Aug 25, 2009 7:39 pmPost subject: Re: H-bond donor/acceptor algorithm and the Rule of 5 Reply with quote

Zsolt wrote:
moses wrote:

Is this still the algorithm that ChemAxon uses? Also, it might be good to note somewhere that this method is not the one Lipinski uses in the Rule of 5:

"There are more than 5 H-bond donors (expressed as the sum of OHs and NHs);
The MWT is over 500;
The 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);"

Best regards,

Moses

Hi Moses,

I think the quoted definition of Lipinski's Rule of 5 is not correct.

Lipinski's rule says that, in general, an orally active drug has no more than one violation of the following criteria:


  • Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)
  • Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)
  • A molecular weight under 500 daltons
  • An octanol-water partition coefficient log P of less than 5

The corresponding Chemical Terms expression is:

(mass() <= 500) && (logP() <= 5) && ((disjointMatchCount('N[H]') + disjointMatchCount('O[H]')) <= 5) && ((atomCount('7') + atomCount('8')) <= 10)

I hope this helps.

Zsolt

Hi Zsolt,

Actually that quote of Lipinski's rule was straight out of his original paper, so I think it's correct. However, your restating of the rule seems to be exactly the same? So I think we're on the same page, I think... : )

Your chemical terms expression is correct, thanks for the pointer on disjointMatchCount().

Moses

Zsolt
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Link to postPosted: Tue Aug 25, 2009 8:07 pmPost subject: Re: H-bond donor/acceptor algorithm and the Rule of 5 Reply with quote

moses wrote:
Zsolt wrote:
moses wrote:

Is this still the algorithm that ChemAxon uses? Also, it might be good to note somewhere that this method is not the one Lipinski uses in the Rule of 5:

"There are more than 5 H-bond donors (expressed as the sum of OHs and NHs);
The MWT is over 500;
The 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);"

Best regards,

Moses

Hi Moses,

I think the quoted definition of Lipinski's Rule of 5 is not correct.

Lipinski's rule says that, in general, an orally active drug has no more than one violation of the following criteria:


  • Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)
  • Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)
  • A molecular weight under 500 daltons
  • An octanol-water partition coefficient log P of less than 5

The corresponding Chemical Terms expression is:

(mass() <= 500) && (logP() <= 5) && ((disjointMatchCount('N[H]') + disjointMatchCount('O[H]')) <= 5) && ((atomCount('7') + atomCount('8')) <= 10)

I hope this helps.

Zsolt

Hi Zsolt,

Actually that quote of Lipinski's rule was straight out of his original paper, so I think it's correct. However, your restating of the rule seems to be exactly the same? So I think we're on the same page, I think... : )

Your chemical terms expression is correct, thanks for the pointer on disjointMatchCount().

Moses

 

Yes, we are on the same page.

Your quotation: "There are more than 5 H-bond donors (expressed as the sum of OHs and NHs)"

Usually used as: "Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)"

Same for the other criteria (molecular weight under/over 500, etc.). It's just some clarification for others forum users, who might get confused.

Regards,

Zsolt

 

 

Jozsi
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Link to postPosted: Wed Aug 26, 2009 12:00 amPost subject: Reply with quote

Hi Moses,

donorCount() and acceptorCount() are not for use
with the Lipinski Rule of 5, because he used a simplified
donor/acceptor count algorithm


   Yes , you are right. We need to emphasize this fact anywhere in the documentation.

 

... Instant JChem the rule of 5 ...when adding a new chemical terms column does use donorCount() and acceptorCount().

...Do you still use that
algorithm, so we can tell our customers that's the algorithm used for
donorCount() and acceptorCount()?

   I can check this tomorrow. I get back asap.

 

  Thanks!

 

Jozsi

Jozsi
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Link to postPosted: Wed Aug 26, 2009 12:25 pmPost subject: Reply with quote

Hi,

Do you still use that algorithm...

Yes.

Jozsi

 

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