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For docking calculations at different values of pH, I am working with flavonoids and would like to know about any software/server that can prepare ligands depending on the pH. Up to now I read about Maestro (Schrodinger) but it is too expensive for us. I wonder if you could suggest other alternatives.

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This is a challenging problem and there are many programs that do this.

One review was published a few years ago: "Comparison of Nine Programs Predicting pKa Values of Pharmaceutical Substances", J. Chem. Inf. Model., 2009, 49 (12), pp 2801–2812

Knowledge of the possible ionization states of a pharmaceutical substance, embodied in the pKa values [...] is vital [...] We compare nine commercially available or free programs for predicting ionization constants. [...] We compared their performances by applying them to 197 pharmaceutical substances with 261 carefully determined and highly reliable experimental pKa values from a literature source. The programs ADME Boxes 4.9, ACD/pKa DB 12.0, and SPARC 4.2 ranked as the top three with mean absolute deviations of 0.389, 0.478, and 0.651 and $r^2$ values of 0.944, 0.908, and 0.894, respectively. ACD/pKa DB 12.0 predicted all sites, whereas ADME Boxes 4.9 and SPARC 4.2 failed to predict 5 and 18 sites, respectively.

Surprisingly, the quantum program did poorly.

There's even a full book on the subject: Computational Approaches for the Prediction of pKa Values by George Shields and Paul Seybold. It covers both quantum and QSAR approaches.

Some of the best seem to be:

But there are dozens out there. I'd check the review articles and try a few.

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  • $\begingroup$ Geoff, thank you for your detailed answer. Could you please point me to some documents describing how Propka can be used for ligand protonation at a certain pH? I need to modify the charge/protonation layer of my ligand at a certain pH according with the predicted pKa value(s). I searched through the web but I find only examples where Propka is used with proteins. I also give it a try but it doesn't give me the expected result. It just gives me a table with the molecule charge as function of pH. That is certainly useful but not what me and the initial question were seeking. $\endgroup$ – green69 Sep 23 '16 at 10:07
  • $\begingroup$ I suggest contacting the authors - including @JanJensen - it's not my code. $\endgroup$ – Geoff Hutchison Sep 23 '16 at 13:41
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For this, you can try to use the LigpKa database server.

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    $\begingroup$ Could you expand on your answer a bit to say why this would be a good choice, please? $\endgroup$ – jonsca Feb 13 '13 at 3:21
  • $\begingroup$ Well, mainly, because it seems as if there is no big spectrum of available software for the task at hand. So it's a good suggestion in that it's maybe the only option. But I have no experience using it. $\endgroup$ – TMOTTM Feb 13 '13 at 9:52
  • $\begingroup$ Understandable. It's just better to have some substance with the answer, as I don't know if you chose it because it has the best XYZ, the most reliable W, or because you like the splash screen. ;) Anyway, anything you know about it would be helpful to future readers of the question, is all. $\endgroup$ – jonsca Feb 13 '13 at 22:55
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you can use also H++ server just go to this link; http://biophysics.cs.vt.edu/

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  • $\begingroup$ Welcome to Chemistry.SE. Take the tour to get familiar with this site. Mathematical expressions and equations can be formatted using $\LaTeX$. $\endgroup$ – Martin - マーチン Mar 6 '15 at 5:20
  • $\begingroup$ I don't think this is exactly what the OP wants - it seems to only handle protonation of macromolecules. The question was for small molecules. $\endgroup$ – Geoff Hutchison Mar 6 '15 at 18:53

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