Re: [Rdkit-discuss] Question about pKa prediction using RDKit

[Greg L. <gre...@gm...>]

I'm slow because of travel... sorry.

I did an implementation of the decision tree using the RDKit not too long
after the original paper came out, when I was stlil at Novartis. It's long
enough ago now that I don't remember the full details. Here's what I do
remember:
- correctly translating the SMARTS patterns took some effort (James'
efforts towards this are captured in the linked email thread)
- I had an email conversation with Adam Lee to clarify some points and, I
think, ended up getting a different version of the decision tree than what
was in the supplementary material. I don't have access to that email any
more, so I could be remembering that last bit incorrectly
- we didn't end up ever using the approach. The limitation that it only
applies to mono-protic species was significant and the fact that bases need
to start in the protonated state (James mentions this in the thread too)

Sorry I can't be more helpful than this,
-greg

On Mon, Oct 16, 2017 at 10:34 PM, Jacob D Durrant <dur...@pi...> wrote:

> Hi Brian. Unfortunately, I haven't gotten any additional responses. This
> isn't a topic you've looked into, is it? Thanks!
>
> On Mon, Oct 16, 2017, 3:37 PM Bennion, Brian <ben...@ll...> wrote:
>
>> Hello Jacob,
>>
>> Have you received any offline replies to this post?
>>
>> brian
>>
>>
>> ------------------------------
>> *From:* Jacob D Durrant <dur...@pi...>
>> *Sent:* Thursday, October 12, 2017 10:21:46 PM
>> *To:* rdk...@li...
>> *Subject:* [Rdkit-discuss] Question about pKa prediction using RDKit
>>
>> I've been struggling to implement the SMARTS-based pKa prediction
>> algorithm outlined by Crippen here: http://pubs.acs.org/doi/
>> abs/10.1021/ci8001815
>> <https://na01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fpubs.acs.org%2Fdoi%2Fabs%2F10.1021%2Fci8001815&data=01%7C01%7Cdurrantj%40pitt.edu%7C9c4fd212d3c841e53cf108d514cd5eee%7C9ef9f489e0a04eeb87cc3a526112fd0d%7C1&sdata=7bEn4YSQZrTDKAEfvg%2BTKhYEOnGTQYlZiQOvRTcPO4Q%3D&reserved=0>
>>
>> This same method has been mentioned elsewhere on this forum:
>> https://sourceforge.net/p/rdkit/mailman/message/27318424/
>> <https://na01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fsourceforge.net%2Fp%2Frdkit%2Fmailman%2Fmessage%2F27318424%2F&data=01%7C01%7Cdurrantj%40pitt.edu%7C9c4fd212d3c841e53cf108d514cd5eee%7C9ef9f489e0a04eeb87cc3a526112fd0d%7C1&sdata=p6uuRMfIjUilI%2BA%2BV3nd3TXNbuK3HanhCG2XiHGv%2Bhg%3D&reserved=0> ;
>> http://rdkit-discuss.narkive.com/jOHraNs8/crippen-pka-model-in-rdkit
>> <https://na01.safelinks.protection.outlook.com/?url=http%3A%2F%2Frdkit-discuss.narkive.com%2FjOHraNs8%2Fcrippen-pka-model-in-rdkit&data=01%7C01%7Cdurrantj%40pitt.edu%7C9c4fd212d3c841e53cf108d514cd5eee%7C9ef9f489e0a04eeb87cc3a526112fd0d%7C1&sdata=iSNXaRzibhcEUwfQg%2FjY%2BjFC26CQaB0NYlxPxJA3R8M%3D&reserved=0>
>>
>> Am I right in thinking that this method has never been successfully
>> implemented?
>>
>> Assuming not, I'm wondering if anyone else has had a hard time
>> reproducing the values listed in that paper's SI using the provided
>> decision tree. For example, consider the compound O(C)c1cc(ccc1OC)C(=O)
>> C(O)=O
>>
>> Running through the decision tree:
>>
>> Node 2: Does contain [#G6H]C(=O)
>> Node 4: Does contain [OH][i](=O)*(~*)~*
>> Node 8: Does contain a[#X]
>> Node 16: Does contain *~*~*~*~*~*~*~*~*
>> Node 32: Does contain [i][#G6v2]
>> Node 64: Does contain [O][i]~[i]~[i]~[i]~[i]~[i]~[i]~[A]
>> Node 129: Does not contain [OH][i]~[i]~[i]~[i]-*
>> Node 258: Does contain [OH][i](=O)[i]~[i]~[i]~[i]-*
>>           Terminal node. 3.1849999 (2.79)
>>
>> And yet the paper lists the decision-tree output for that molecule as 1.8.
>>
>> Am I missing something obvious? I'd appreciate any help the community
>> could offer. Having a basic pKa predictor in rdkit would be so useful...
>>
>> Thanks!
>>
>>
>>
>> --
>>
>> Sent from my mobile.
>>
> --
>
> Sent from my mobile.
>
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