From owner-chemistry@ccl.net Fri Jul 11 19:29:00 2008
From: "Marcus Gastreich support%biosolveit.de" <owner-chemistry**server.ccl.net>
To: CCL
Subject: CCL: Protein-Ligand CONSTRAINED Docking
Message-Id: <-37331-080711115119-13352-1/MK9Bzqoyb/7MwU6CsAjw**server.ccl.net>
X-Original-From: "Marcus  Gastreich" <support]*[biosolveit.de>
Date: Fri, 11 Jul 2008 11:51:15 -0400


Sent to CCL by: "Marcus  Gastreich" [support,,biosolveit.de]
hello richard-

thanks for asking - i am confident that flexx 3.* with its own GUI 
will be very much up to your standards. ;-)

it's freely downloadable from 
  
  www.biosolveit.de/download

and will check out a license only once you press "Apply & Dock!".

in flexx-pharm, there are some ways to achieve what you want

a) you can constrain a SMARTS subgraph expression in such a way that
 only one specific nitrogen will match the expression and thus
 be allowed to be placed in a very "spatial constraint" (i.e., the
 sphere you define). so, the spatial definition possibilities go
 beyond the pure "element". multiple, overlapping spheres should
 give you the freedom to play with as many distances as you require.

b) there is a biosolveit extension to smarts implemented which 
  allows you to use sybyl atom typing in smarts. it uses curly braces, 
  e.g., [{C.2}]  

c) place manually, then grow.
 in flexx's core facility there is the possibility of placing one 
 part of your molecule and then let the rest grow automatically. 
 this can, e.g., be used for docking families of compounds which 
 share a common part which places in a similar way. but here, you could
 use the mechanism to place an imiadzole just in the way you like, then 
 let flexx/-pharm do the rest. not yet supported by the gui, but 
 still easily doable:

  http://www.biosolveit.de/tipsntricks/archive/mapref.html

finally, maybe not exactly what you need in your specific case, but
please note that there are also the "interaction type" constraints.
so you could say "i need to see this acceptor interaction with LEU 83"
the GUI will guide you a lot in doing all this; in addition it has on-the-fly smarts checking,
so you will hopefully not have a hard time coming up with even more
complicated expressions. the procedure is

1) load pdb
2) define receptor
3) define pharmacophore

btw-
the pharm. can also be exported and then used by other tools, 
e.g., MOE, Sybyl, and an exported PipelinePilot component.

i hope this helped. did it?

very cordial greetings-

  marcus


Richard Wood rwoodphd:+:msn.com schrieb:
> Sent to CCL by: "Richard  Wood" [rwoodphd##msn.com]
> Hi all,
> 
> I have a series of ligands which I've docked to a protein using 
> Surflex-Dock as implemented in Sybyl.
> 
> Unfortunately, my results don't explain some experimental observations 
> so I would like to do some contrained docking.
> 
> I've been looking into FlexX-Pharm, but it seems to only allow one to
> constrain an ELEMENT of the ligand to be a certain radius from a
> certain atom (which one can choose) in the protein target.  For
> example, one can pick a nitrogen in a ligand to be within a 3.0
> Angstrom radius of a given protein atom, say.
> 
> This is problematic if your ligand has several nitrogens or carbons in 
> them, as one cannot pick atom types or atom numbers.  I'm wondering if 
> there is a workaround to this; I'd like to stay with Sybyl as my boss 
> wants me to use it, and we've decided Glide is not up to our standards. 
> 
> To conclude, I would like to be able to pick a particular ligand atom and
> constrain it to be a certain distance from a protein atom, that I again
> pick, and then dock it.  As it stands now, I can only constrain a (any)
> nitrogen in my ligand (I think the fact that my ligand is not
> introduced at any point, prior to docking, into this process is what is
> problematic) to be within a radius of a protein atom, and not a fixed
> distance.
> 
> Basically, I want to constrain an imidazole nitrogen
> (say) to be 2.4 Angstroms away from an iron atom in a heme group, or a
> methyl group to be 3.0 Angstroms from the same atom, and not WITHIN a
> radius of this distance, since it can be anywhere from 0 to the
> distance I want, and lead to situations I'm seeing now, where the
> molecule I'm docking is on top of the heme.
> 
> TIA,
> Richard
> 
> 
>