Subject: Summary: Docking of Covalently Bound ligands

From: "David Turner" <[email-masked]>
Date: Tue, 12 Jun 2001 17:04:18 +0200

Dear all

Original message:

Can anybody point me to some overviews/discussions of the
docking of ligands that are (or are potentially) covalently
bound to the receptor site. I am looking at this mainly
but not solely from the view-point of high throughput virtual
screening.

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From: Suzie Byun [[email-masked]]
Hi David,
I saw your posting on ccl regarding docking of covalent ligands.  I
did a project on this very topic.  I had a crystal structure of an
enzyme-ligand complex and I had to dock ligands back into the active site.
Of course the vdw contacts makes this prohibitive to dock back in
non-covalent ligands.  There are two programs I am aware of that can
dock covalent ligands.  The first I have only read about - GOLD which in
the literature claims to be able to do the job.  THe second program, I
have had direct experience with and promising results.  THe program is
called Dockit, from Metaphorics Inc. in Northern California
(I believe).  I used Dockit to re-dock the original ligand
back into the crystal structure and within the top 5 best scorers, the
rmsd of the fits were around 1.5-2 Angstroms.  The program works by
specifying 1-2, 1-3, and 1-4 close contact distances.

Anyway, there is a website you can check out if you are interested. Please
let me know if you are.
Good luck, Suzie

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From: David Clark [[email-masked]]

Hi Dave
Saw your question on CCL - the Agouron approach to this was described in:
Gehlhaar, D.K., Bouzida, D. and Rejto, P.A. Reduced Dimensionality in
Ligand-Protein Structure Prediction: Covalent Inhibitors of Serine Proteases
and Design of Site-Directed Combinatorial Libraries. In Rational Drug
Design: Novel Methodology and Practical Applications, ACS Symposium Series
Vol. 719, Parrill, A.L., Reddy, M.R., Eds.; American Chemical Society:
Washington DC; 1999, pp. 292-311.

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From: Joe M Leonard [[email-masked]] - Tripos
David, I have always felt that covalently-bound ligands are
less a docking than a conformational analysis problem - and
the tool set for the latter is more extensive.  Are you trying
to vHTS a set of compounds with a known positioning in the
cleft?  If so, QM/MM calculations seem way too slow to actually
handle the electron/proton motion...

We get a lot of people purchasing FlexX to vHTS arbitrary collections
of molecules, but they usually don't know what the active site
configuration would be.  There are a few who want to specifically
position individual ligands, but that's a bit more work and usually
has to be done molecule by molecule (making any automation difficult).
The DOCK literature might cover this, as there have been a number
of articles over the last few years from Kuntz and folks.

Joe

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From: Dave Young [email-masked]
>
> David,
>
> Most docking programs are designed for non-covalently bound ligands,
> which have been the focus of structure based drug design.  I am aware of
> two commercial programs that can have the ligand attached to the active
> site.  One is GOLD (http://www.ccdc.cam.ac.uk/prods/gold/index.html) and
> the other is DockVision (www.dockvision.com).  Both of these allow the
> user to define an attachment between the ligand and the active site.
> However, it is a geometric constraint only...neither attempts to include
> the covalent bond energy in the binding energy.  This can be a problem
> since you can find a large range of covalent binding energies depending
> upon whether it is an irreversible bond formation, or a reversible
> partially-covalent adduct formation.
>
> The only program I'm aware of that does a covalently bound docking
> including the covalent bond energy is a QM/MM docking algorithm that I
> wrote here at Cytoclonal Pharmaceutics.  This is one piece of Quantum
> Core Technology (QCT), which is a mechanism based drug design system
> proprietary to Cytoclonal.  This software is not available commercially,
> but Cytoclonal is interested in business partnerships with other
> corporations to utilize this technology.
>
> Let me know what solution you come up with for this problem.
>

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