Subject: LEAPFROG

From: Richard M Day <[email-masked]>
Date: Fri, 16 Jul 1999 11:52:05 +0100

Dear Kathe, and the LEAPFROG user fraternity.

Earlier this year I sent an EMAIL to the CCL, regarding the reliability of
the LEAPFROG binding free energy calculations for ligand ranking and you
were kind enough to email me with some answers.

I have been using LEAPFROG for a while now to try and propose some xxxxxx
binding ligands using oligopeptides as the initial approach.  Well to be
completely honest none of the dozens of peptides proposed by LEAPFROG
worked at all.  This is a problem for me,because my PhD was to use de novo
and rational design to try and find something.  In the end I rationally
designed a xxxxxxx with xxxxxx (censored) amino acids and this seems to
work splendidly, phew...

The key problem now is WHAT WENT WRONG ! and how could this be improved upon ?

I have been trying to find literature where LEAPFROG has been evaluated,
tried and tested by reproducing known ligands in binding site.  I have
access to a very powerfull literature tool known as BIDS (based at Bath
Uni, UK. www.bids.ac.uk) this has the abstract of every quality journal
since 1980.  

We cannot find a single reference that refers to LEAPFROG. 

Talking to the UK technical support at Tripos, the algorithms in LEAPFROG
are proprietary and therefore information on the precalculation of
interaction points, empirical binding scoring mechanism, forcefields used
if any, means of geometry optimisation and so forth, are not available for
the world to see.  The only information I can find is a list of authors on
the first page of LEAPFROG and some quite old references at the back.

If LEAPFROG is based on the assumptions from these old references (after
our  literature research, these assumptions are often have several flaws,
of which many have been addressed in later versions) then this program is
due some severe maintainance, of which we assume is already done since this
is a proprietary program. But has it ?! If this has been done then why not
tell us exactly what assumptions it uses ! and to top that, give us the
references that they have based the algorithm so we can use both chemical
insight with more understanding where and why the algorithms propose
non-sensible solutions.

There have been some quite fantastic developments in de novo design
recently, including CONCEPTS, BRANCH&BOUND, PRO_LIGAND.  Why has not
LEAPFROG adopted some new ideas ?  

I have heard from several sources that nobody is too bothered with de novo
design today, but prefer VHTS with databases for initial lead finding. Even
construct 3D stuctural databases with your own designer diversities.  

Databases of proprietary drug leads may contain upwards of 500,000
compounds, but these have been sourced from complexes with active centers
often in deep clefts within proteins. What happens if you want to look at
active sites with only quite shallow binding clefts or even surface binding
sites.  I cant imaging many compounds from such a database being a lead or
"provoker" for such a surface borne active site.  

Well make your own database of structures and dock them !!
-=-=-=-=-=-==-=-=-=-=-=-=-=-==-=-=-=-=-=-=-=-=-=-=-=-=-=-=-

How are you supposed to design a diversity library for VHTS if you dont
know where to take your "base" structures from ?  Answer, the use of a de
novo tool.  The arguement that de novo design techniques are not worth
developing because nobody wants them, is misguided.

So to put it overly bluntly. 

Where is LEAPFROG 1999, to go with the maintenance fees ?

Yours Faithfully,

Richard Day.

---

From: Mark Forster <[email-masked]>
Date: Fri, 16 Jul 1999 15:09:08 +0100

Dear Richard

This posting touches on a theme that was raised in a question a few days ago
discussing the differences between protein secondary structure prediction in
Weblab Viewer (MSI) and Rasmol. The issue is one of the publication of the
underlying algorithm within a piece of code. It is this that represents the real
intellectual input and needs to be visible, in order to be judged, when the method
is used as part of a scientific publication. Weblab Viewer and Rasmol may
use somewhat different algorithms, they may have different behaviour, but at least
the Rasmol code is available and anyone who is interested can study the code,
work out what is happening, and posibly even improve the method. If the code
is not available then the onus is on the program supplier to document the program
to such an extent that the algorithm is clear. In fairness to MSI they are document

most of their programs to a high level of detail. I cannot comment on Leapfrog as a

specific case, but if the vendor claims a method to be proprietary, and the
algorithm
is not described in detail, or at all, then the buyer only has the performance on a

limited number of test cases that they can use to evaluate the product. Caveat
Emptor.

Bye for now,

Mark F

Richard M Day wrote:

> -= 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]

--

  Dr Mark J Forster Ph.D.
  Principal Scientist
  Informatics Laboratory
  National Institute for Biological Standards and Control
  Blanche Lane, South Mimms,
  Hertfordshire EN6 3QG, United Kingdom.

  Tel  +44 (0)1707 654753
  FAX  +44 (0)1707 646730
  E-mail  [email-masked]

---

From: Richard Gillilan <[email-masked]>
Date: Fri, 16 Jul 1999 10:14:09 -0400

Richard M Day wrote:
.
.
.
> construct 3D stuctural databases with your own designer diversities.
.
.
.
> The arguement that de novo design techniques are not worth

I'd be interested to hear from others about this. Is de novo
design passe? What do most groups use docking for?

Richard Gillilan
Cornell Theory Center