[Dock-fans] Is the following a reasonable application for DOCK? (Filtering/screening scheme)

Silberstein, Michael mikesilb at bnl.gov
Thu Sep 27 08:01:47 PDT 2007

Hi all,


I have a question regarding a particular docking application, and I would like to get a sense as to whether DOCK is a

 reasonable program for implementing such an application, or if other docking programs might be better served.


I would like to perform virtual screening (using a mini-library of approximately 100,000 compounds) on a number of target

 crystal structures (approximately ten structures in all).  The architecture of the substrate-binding pocket of each of these

 structures is generally quite similar; however, small sub-regions of the pocket are, nevertheless, different/unique in order to

 accomodate specificity differences amongst the various ligands/substrates that will bind to each individual protein.


I am aiming to find "common inhibitors" that will be capable of binding ALL of the structures with reasonable binding

 affinities (rather than to find separate inhibitors for each target protein).  The protocol by which I was hoping to identify such

 "common inhibitors" is the following:



Step 1:  Dock all 100,000 to target structure #1 using DOCK.  Based on DOCK's bump filter and scoring function, only a

 certain subset of the 100,000 compounds would provide docking output, while the remainder (that might have too many

 bump clashes, etc.) would be skipped.


Step 2:  Dock the remaining (unskipped) compounds into target structure #2.  As in Step 1, some molecules will be

 skipped and others will be retained.


Step 3:  Dock the remaining compounds (i.e. the ones retained after Steps #1 and #2) into target structure #3.  Some

 molecules are further retained.  Others are not.





Step N:  Dock the compounds (that have been retained after docking to the (N-1) targets) to the final target structure.  Only 

those remaining compounds that are retained after this final docking step can be used in subsequent studies in order to 

further narrow down this subset and identify the inhibitors common to each of the (N) proteins.




My question is whether or not DOCK can be used to implement the above protocol and to filter out (after each step) the

 molecules that do not appear to dock well from the remaining molecules in the initial mini-library?  Or might an alternative

 docking program be better served for this application and protocol?


Thus far in my usage of DOCK (both v4.0.1 and v6.1), I have found that the VAST majority ( >99%) of compounds have been

 retained (and not skipped), which has made me question the feasibility of performing this "filtering" analysis using DOCK.  


Also, is there a way to increase the "stringency" of DOCK (either based on scoring function selection, bump filter, or other

 parameters) so that fewer compounds can be retained from step to step? 


If anyone is able to address these particular issues/questions, I would greatly appreciate it.  Thanks in advance.




Mike Silberstein




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