[Zinc-fans] requesting peer suggestions on docking and duplication

[John J. Irwin]

Dear Elite158

Thank you for your interest in ZINC.


>
> Considering an enzyme that is reported to be optimum at a pH of 
> 7.6-8.0, which we intend to find inhibitors for, which subset of ZINC 
> compounds do I chose for docking against my target of interest?
I recommend subset the reference form at pH 7 (called "ref") as well as 
the additional forms at physiological pH (called "mid") 5.75-8.25. This 
is available for download via the "usual" download link on the ZINC 
download pages.

>  
> (/Why was there a need to create these subsets based on pH of ligands 
> in ZINC database? Please educate if time permits/)
Metalloenzymes deprotonate thiols, sulfonamides, and hydroxamic acids, 
for example. Thus you must create the deprotonated forms to "get the 
right answer for the right reasons". See Irwin JJ, Raushel FM, Shoichet 
BK, "Virtual screening against metalloenzymes for inhibitors and 
substrates.", Biochemistry, 2005, 44(37),12316-28. DOI 
<http://dx.doi.org/10.1021/bi050801k>.'

At the other extreme, the W191G mutant of cytochrome C peroxidase 
requires compounds that are not normally protonated, such as anilines. 
See Brenk R, Vetter SW, Boyce SE, Goodin DB, Shoichet BK. Probing 
molecular docking in a charged model binding site. /J Mol Biol/* 357* 
(5), 1449-70 (2006). [Pubmed 
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16490206&query_hl=4&itool=pubmed_docsum> 
| DOI <http://dx.doi.org/10.1016/j.jmb.2006.01.034> | Download PDF 
<http://shoichetlab.compbio.ucsf.edu/publications/brenk_jmb_2006.pdf>]

It is a small step from these two extremes to creating pH dependent 
subsets. We realize this is not an ideal solution, but it has helped in 
our own work.

>  
> *_Scenario 2_*:
> Another question is with handling duplicates in ZINC Libraries. The 
> automated docking protocol we are currently using requires all the 
> Zinc comounds (if we are interested to dock a whole subsets of 
> drug-like, fragment-like etc,) to be present in one single sdf file. 
>  
> As John wrote a reply sometime back in July 2006 for a query on 
> duplicate structures, one would definitely not be interested in 
> removing the duplicates
>  
> "... it is perfectly normal to have more than one representation of a 
> molecule if you combine all the files. For example, imidazole would 
> have one representation (e.g. protonated) in the p0 "reference" 
> subset, and have the neutral form in the p1 subset..."
>  
> The question is, if we merge all the files into one single giga SDF 
> file, are the ZINC IDs unique to all the entries, meaning, can we 
> safely traceback the ligand of interest to its representative pH subset?
>  
We have done extensive duplicate removal ("retirement") in ZINC 8 
(http://zinc8.docking.org/). I won't say there are no duplicates, but 
the number is way, way down. ZINC 7 remains unchanged (including 
duplicates) for backward compatibility with projects already in 
progress. ZINC 8 is not the official release yet, but it will be soon.


Good luck

John
UCSF ZINC Team

<http://shoichetlab.compbio.ucsf.edu/publications/brenk_jmb_2006.pdf>
>  
> With best regards,
> Elite158
>  
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