ADL: term"randomized structure"

Richard Wood Richard.Wood at purduecal.edu
Sun Mar 27 06:26:18 PDT 2016


A couple of years ago, I docked a molecule to one of the malaria targets.  I forget which software I used (it might have been Dock, but I am not certain; I do know it was one of the programs that runs under Windows), and the software got the location right, but the molecule was UPSIDE down.  I am pretty sure the RMSD was low (maybe around 2) but the orientation wasn't right.  

That is why I wrote what I did about geldanamycin.  I was working on a project targeting HSP90 a few years ago (we were actually trying to develop some new anti-breast cancer agents) and when I started, the first thing I did was pull geldanamycin out of the crystal structure with HSP90 and re-dock it.  By playing with the docking parameters, I was able to dock it in the correct place and with the correct orientation and the RMSD was 0.4.  The young scientist that I talked to about his talk most likely just used the default settings in the docking program he used (Glide perhaps?); he seemed to not know that he could adjust the settings.

Another thing you neglected to mention is that some programs (Surflex in particular) take a compound, break it into fragments, dock the fragments and then optimize the results (ie., the recombined ligand).  Thus, docking a macrocycle should not be a problem for a modeler.

Richard
________________________________________
From: autodock-bounces at scripps.edu [autodock-bounces at scripps.edu] on behalf of Stefano Forli [forli at scripps.edu]
Sent: Saturday, March 26, 2016 2:32 PM
To: autodock at scripps.edu
Subject: Re: ADL: term"randomized structure"

Richard,
your reply sparks interesting discussion topics.

>I don't agree with the "within 2.0 A range you can assume that most of the known essential interactions with the target have been
>established" comment.  That would mean that a molecule such as geldanamycin could have completely flipped its orientation.
I'm not sure this would be the case, actually.





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