alkaline alkaloids...

The pka calculator returns only 6.8 for the following alkaloid:





COc1cc2N3C(=O)C[C@@H]4OCC=C5CN6CC[C@@]7(c2cc1OC)[C@@H]6C[C@@H]5[C@@H]4[C@H]37





which may actually be morphine if my neuron still remembers the MedChem courses. If this is so, its actual pKa should have been about 8 - but I noticed that in general you don't like tertiary amines to show up as protonated at pH=7 (at least according to pharma-frag.xls). Please allow me to protest in the name of the ad-hoc founded Association for the Freedom of Protonation! This is even more puzzling in sight of the otherwise excellent performance of the pKa predictor, which was able to correctly predict a pKa of 10 for N-Ethylcyclohexylamine and an INCREASE to 10.9 in the bicyclooctylamine having N as a bridge head! Now that is cool 'cause one of the reasons for lower tertiary amine basicity is the strain required to force substituents into a honest tetrahedral geometry upon proton binding, which is not applying to bridgehead amines with substituents already coerced to sit straight. So why is morphine altering the state of mind of the otherwise so clear-sighted pka plugin?

Hi Dragos,





may we join the AFP?!





If you look at the documentation of pharmacophore type recognition in doc/user/PFp2D.html (or http://www.jchem.com/doc/user/PFp2D.html) then you can see that we have already founded the Association of the Hydrogen Bond Donor Atoms with a valuable member called tertiary amine.





We are so smart, that even the Assoc. for the Ugly Exceptions to THE Rule has also been set up.





Regarding pharma-frag: yes, you are right that pharma-frag does not recognize tertiary amines as being protonated at ph 7. It used to work all right for amines ... but some evil forces changed the file on our server. I'll strike back and fix it in the next release.


Thanks for telling!!





Regarding the pKa calculator you'll receive a separate response.





Regards


Miklos

Hi,





Thank you for the details about trouble of alkaloid pKa calculation.


Bug have been fixed.


Predicted pKa of Brucine is 7.8.








Improved pKa release will come as soon as possible.





Best wishes ,





Jozsi