ADL: question about Vina flexible residues and pockets

Witold Witkowski wwitkowski at bostonbiomedical.com
Wed Jan 22 11:01:01 PST 2014


...(Also, it's believed that about 1/3 of all bound ligand X-ray structures are completely wrong)... [Citation Needed]


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From: autodock-bounces at scripps.edu [autodock-bounces at scripps.edu] on behalf of Oleg Trott [trott at scripps.edu]
Sent: Wednesday, January 22, 2014 1:10 PM
To: autodock at scripps.edu
Subject: Re: ADL: question about Vina flexible residues and pockets

Hi

I'm assuming that you want to evaluate the suitability of Vina as a
virtual screening method for your system.

To do that, you could do a retrospective VS on known binders and
either known non-binders or random decoys, kind of like what the
Directory of Useful Decoys offers (Vina results linked from the Vina
web site and manual). If it sounds too tedious to do by hand, I think
PyRX can automate it, and make ROC plots for you.

The ease of fishing for a few predicted bad binders seems difficult to
interpret.

"Score_only" of X-ray structures probably shouldn't be used to
estimate the binding affinity: for all we know, there is a 10kcal/mol
better energy 0.1A RMSD next to it. (Also, it's believed that about
1/3 of all bound ligand X-ray structures are completely wrong)

On Wed, Jan 22, 2014 at 9:24 AM, Dennis N Bromley <dbromley at uw.edu> wrote:
> Hi everyone,
>
> I am having a problem because practically any ligand that I throw at my
> pocket seems to dock with reasonable energy and it seems that that should
> not be the case.  Here is what I am doing:
>
> I used a pocket-finding algorithm (epos ball-pass) to find a pocket in my
> protein and now I want to use Vina to find a ligand that will bind tightly
> to it.  I set my search box to be centered around the pocket plus an extra
> 5 angstroms in each direction for padding.  I then set all of the
> pocket-lining residues to be flexible, convert a huge stack of ZINC ligands
> to pdbqt using OpenBabel, and dock them in.  My pocket is ~430 cubic
> angstroms.
>
> To date, the worst energy I have gotten is -5.9 kcal/mol.  The best I have
> gotten is -12.1 kcal/mol.  For reference, the drug celebrex in xtal holo
> position docks into COX-2 (PDB:3LN1) with -10.6 kcal/mol (using
> --score-only) and various bits of literature show Vina energies of vitamins
> and such around -9.  So, these values seem like they might actually
> potentially bind.
>
> The problem is that I can't find a bad docker for the life of me, which
> makes me question my good dockers.  My pocket is an internal pocket in the
> hydrophobic core of the protein (as is my comparable, Celebrex) so I
> searched ZINC for the most awkward polar molecule I could find and it still
> came in at -9 kcal/mol.  I can't even match my -5.9 molecule; literally
> random picks still score in the -7 to -8 range.
>
> Any ideas what I am doing wrong?  Am I misinterpreting "good energy"?
>  Should I not be using flexible residues?  There are about twenty residues
> in the pocket - does that provide so much freedom that it will adjust for
> just about any ligand?
>
>
> Thank you!  I appreciate any insights - something is amiss here that I am
> not seeing.
> Denny
> ________________________________________________
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--
Oleg Trott, Ph.D. (Columbia University)

Staff Scientist in the Olson Lab
The Scripps Research Institute

http://olegtrott.com
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