Subject: QXP summary

From: Oliver Hucke <[email-masked]>
Date: Wed, 27 Feb 2002 09:06:35 +0100

Dear CCLers,

This is the collection of all answers to my question concerning the drug
design program QXP.

Many thanks to

Holger Claussen
Joe Leonard 
Mohan
Teran Castañon, Hugo Gutierrez de
David Turner
Pieter F.W. Stouten 
Ya-Jun Zheng

for their replies!

	Kind regards,

	Oliver

____________________________________________________________________________

Oliver Hucke
Inst. fuer Physikalische Chemie II
Universitaet Freiburg
Albertstr. 23a
D-79104 Freiburg

Tel. :  +49-761-203-5130 (/-6179)
Fax. :  +49-761-203-6189
email:  [email-masked]
____________________________________________________________________________

My CCL-message:
==================

Dear CCL'ers,

we are interested in methods for ligand docking calculations and
structure based drug design in general.
We have used mainly the ligand docking program FlexX so far, but we
would like to be able to treat the binding site as conformationally
flexible - FlexX uses a rigid binding pocket. Somebody pointed us to the
package QXP, but there is only very few information about it on the
internet. Therefore, we would like to ask you for some information about
QXP.

Do you have any experience with QXP, especially with its ability to
perform ligand docking calculations with flexible protein binding site
and with the accuracy of predicted binding free energies?
Could you point us to some papers describing QXP applications or other
sources of information about the program?

Thank you very much in advance,

Oliver

Replies:
====================

---------------------------------------------------------------------------

Hello Oliver,

>Do you have any experience with QXP,
>
Yes. In fact, we think it is so good that we recently concluded a global
agreement so that our research sites in St. Louis, Chicago, Kalamazoo
(USA)
and Nerviano (Italy) have unlimited access and can run an unlimited
number
of simultaneous QXP jobs. We are in fact in the process of purchasing
two
Linux clusters with the specific aim to run QXP on them.

>especially with its ability to
>perform ligand docking calculations with flexible protein binding site
>and with the accuracy of predicted binding free energies?
>
Well, that's the holy grail, isn't it? In order to obtain correlation
with
experiment, one often has to scale the various energy terms and even
then
the results are not always satisfactory. Colin McMartin is about ready
to
release a new scoring function that is based both on crystal structure
data
and on inhibition data of congeneric sets of compounds. In terms of
docking
quality (i.e., the ability to reproduce known binding modes), we find
that
often QXP finds the correct mode (among, say, the best 10-20 poses), but
does not score it highest. Both docking and scoring quality also depend
to a
large extent on the target under consideration. Another docking program
you
might consider is MolSoft's ICM, whose scoring function has been
optimized
such that "actives" and "inactives" are separated as much as possible. 

>Could you point us to some papers describing QXP applications or other
>sources of information about the program?
>
I saw two back-to-back presentations at the 219th ACS meeting in San
Francisco (March 2000), one by Dominic Ryan of SKB and one by
Venkatraman
Mohan of Isis Pharma. They both prominently featured application of QXP
and
both speakers were quite positive about their experiences.

In terms of ease of use QXP/Flo surpasses anything I have seen. It is
clearly designed and developed for modellers by a modeller (who got
frustrated with generally available tools and decided to build his own).

Hope this helps,

Pieter

Pieter F.W. Stouten, Ph.D.
Head, Computational Sciences
Department of Chemistry
Pharmacia Italia, Nerviano (Mi), Italy
Phone:  +39-02-4838-5227 (secretary: 3962)
Fax:    +39-02-4838-3965
Mobile: +39-348-260-3380

-------------------------------------------------------------------------------
Lieber Herr Hucke,

in der CCL fragen Sie nach Docking Programmen, die das Docking in
flexible 
Proteinstrukturen erlauben. Ich habe eine Erweiterung f"ur FlexX  names
FlexE 
entwickelt, die Proteinflexibilit"at behandeln kann.

Im Monet bin ich dabei den Prototypen von FlexE zu "uberarbeiten. 
Eine kostenlose Demoversion von FlexE soll es demn"achst geben.

Ich habe mir erlaubt einen Artikel "uber FlexE anzuh"angen und w"urde
Sie informieren, sobald es die Demoversion von FlexE gibt.

Viele Gr"usse

Holger Claussen 

=============================================================================
 Dr. Holger Claussen
 
 Fraunhofer-Institute for                       
 Algorithms and Scientific Computing (SCAI)     BioSolveIT GmbH
 Schloss Birlinghoven                           An der Ziegelei 75
 D-53754 Sankt Augustin                         D-53757 St. Augustin
 
 Tel: +49 - 2241 - 14 - 2795                    +49 - 2241 - 973 66 65
 Fax: +49 - 2241 - 14 - 2656                    +49 - 2241 - 973 66 88
 E-mail: [email-masked]    
[email-masked]
 Internet: http://www.scai.fraunhofer.de        http://www.BioSolveIT.de

-------------------------------------------------------------------------------------

Hello Oliver, 
Yes, we did use QXP in our group for the docking of ligands on models of
GPCRs. The accurancy of the energies is not good, but you can
use its energie values for a first ranking of the ligands. 
The program has a graphical interface (called LZM), which you can use to
prepare your docking search (i.e., starting position, flexible
sidechains, distance constraints). This last point is crutial for a good
search, or in adition you can  define a grid for the search, what never
worked for me. It has several modules (TFIT for a pharmacophore search,
MCDOCK for docking, and DINDOCK for a MC-simulated
annealing). I only have experience with the first two. After preparing
the files, you can run it on the LZM interface or in shell mode (it
works
better). 
Here is the reference of the program: 
Mcmartin,  Journal of Computer-Aided Molecular Design 11(4): 333-344;
Jul 1997), and there is another reference (Carrieri et al,
Proteins, 43:382 394(2001)), where you will find a good description of a
docking with QXP. 
The program only works for SGI, and you have to order it to the author.
I'm afraid the support is not too good. 
Hope this helps. 
Fell free for any comments, 
Best regards 
Hugo 
  
----------------------------------------------------------------------------------------

Oliver, if you have Tripos/Sybyl Biopolymer's module, you can look
at FlexiDock - it's a GA-based docking code which allows for both ligand
and protein flexibility.  You might also want to look at GOLD, although
I'm
not sure how one gets it...

Joe

-- 
Dave Young wrote:
> 
> Hi,
> 
> A number of CCL members have asked about the book I have been writing.  It is now in print and available from Wiley.  Here is the publisher's description.
> 
> COMPUTATIONAL CHEMISTRY
> Applying Computational Techniques to Real-World Problems
> 
> David Young, Cytoclonal Pharmaceutics, Dallas
> 
> 0-471-33368-9           Pub Date: 2/16/01               416 pages               $69.95
> 
> As the field of computational chemistry continues to expand, experimental chemists are expected to know how to utilize techniques that are becoming available at the desktop level through commercial software packages. This book provides a much-needed basic guide to computational chemistry software and tools available today.  A practical, easily accessible reference for chemists, this text focuses on accurately applying computational chemistry techniques to everyday chemistry problems.  Techniques for handling problem cases, such as SCF convergence problems, are also discussed.
> 
> To order, please call (800) 225-5945 or visit http://www.amazon.com/exec/obidos/ASIN/0471333689
> It is also available through Barnes & Noble (http://www.barnesandnoble.com/), which has the table of contents listed on the web.
> 
> Dave Young
> [email-masked]
> 
> -= This is automatically added to each message by mailing script =-
> [email-masked] -- To Everybody  | [email-masked] -- To Admins
> [email-masked] -- HELP CHEMISTRY or HELP SEARCH
> [email-masked] -- archive search    |    Gopher: gopher.ccl.net 70
> Ftp: ftp.ccl.net  |  WWW: http://www.ccl.net/chemistry/   | Jan: [email-masked]

-- 

Hi Oliver:

Here is the QXP reference:

C. McMartin & R.S. Bohacek
J. Comput.-Aided Mol. Des. vol 11, 333, 1997.

McMartin's e-mail address:
[email-masked]

His telephone number:  860 379 5502

Let me know if you need any additional info.

Cheers,
-mohan

--------------

Hi again,

You could also get information on QXP at
http://uwmml.pharmacy.wisc.edu/Flo/floindx.html

-mohan

---------------
Ya-Jun Zheng wrote:
> 
> Oliver,
> 
> QXP is part of Flo99, which is a program developed by Colin McMartin and
> Regine Bohacek.  There are a number of papers describing the modeling
> results using Flo.  Please see the recent papers by Dan Rich in J. Med.
> Chem. (in 2002)  and Organic Letters (in 2001) and also papers by Regine
> Bohacek and coworkers from ARIAD Pharmaceuticals (works on SH3 domain
> inhibitors, some appeared on covers of J. Med. Chem last year).  Regine
> also developed a de novo design program (called AlleGrow) recently.  Here
> is Colin's contact info:
> 
> Phone: 860-379-5502 and e-mail: [email-masked]
> 
> Yajun Zheng