[Dock-fans] Fixing protonation state

burgosgu at ualberta.ca burgosgu at ualberta.ca
Sat Nov 3 14:14:40 PDT 2007

Hi John and Francesco,

I guess it's time for me to write. Thanks a lot for your explanations.

Well, actually that compound has been found to be the most powerful in  
vitro inhibitor for the enzyme with which I'm working. I wanted to  
dock it as a validation for the parameters I chose for the docking  
program (AutoDock). If the score thrown by AutoDock for this compound  
was higher than for most of the ligands then I could assume that the  
predictive ability of AutoDock with those parameters is fairly good. I  
actually docked this compound with very good results (predicted energy  
of binding = -10.83 kcal/mol). The structure I used was one that I  
drew myself with Pymol builder based on the paper that mentioned that  
it was a powerful inhibitor. But, I realized that I couldn't compare  
this value with the  predicted energies of binding for my drug  
candidates because they were all ZINC structures. So, the ZINC  
compounds had a correct protonation state while my compound didn't.  
That's why I tried to use ZINC upload sets resource.

So, in my particular case it would be very helpful that ZINC gave back  
a structure with the correct protonation, probably with a note that  
the compound broke the rules.

Thanks again,


Quoting "John J. Irwin" <jji at cgl.ucsf.edu>:

> Francesco
>>> But given the famously high false positive rate of docking, the odds are
>>> against you.
>> Is any criterion to detect, or suspect (on the basis of DOCK + Amber) false
>> positives?
> That would be very useful! I can see how to rule *out* compounds by
> coding up the same rules of thumb we use when looking at top scoring
> hits (good overall steric, hydrophobic and shape complementarity,
> penalize stranded polarity, and missed opportunities in the
> protein-ligand complex. But I see this more as "getting rid of junk"
> rather than pretending to scrupulously eliminate false positives.
> John

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