Subject: RE:POSTED RESPONSES: Quantitative assessment of novel ligand

From: [email-masked] (Marvin Waldman)
Date: Wed, 28 Jun 1995 18:47:04 -0700

Dear Netters,

On June 28, 1995, Michael Dooley posted a number of responses to
his original post about software packages that can predict binding constants:

>>I'm searching for a protocol or recipe of 'vital statistics' to assess
>>novel ligands that i've designed, so that i'll have firm arguments to
>>convince organic chemists to synthesise a molecule.  I'm using biosym
>>software + intuition to de novo design ligands for a target with good
>>x-ray data and also have access to Oxford Molecular software.  If it
>>might not be possible to roughly predict binding constants for novel
>>compounds that differ greatly from known ligands, are there methods to
>>predict the effects of modifications to known ligands.  I'm aware of
>>scoring functions such as Bohm Comput-aided mol des (1994) 243, but I'm
>>not sure if this would be appropriate. Eagerly awaiting any suggestions.

Among the posted responses was the following message from Dick Cramer:

>There are probably over a hundred citations for the use of CoMFA
>as a tool for predicting biological activities (conversely I know
>of none for BioSym or Oxford Molecular save that of Boehm and
>Richards, the developers). If you are involved with known receptor
>structures, some of the work by Garland Marshall and his collaborators,
>for example in JACS, might be relevant. Sorry I don't have specific
>referebnces handy --
>   yet another biased developer, Dick Cramer
>
>[email-masked]

I would just like to make a minor correction to this posting.  In
fact, a publication on the application of Hans Boehm's Ludi program
to de Novo design problems from an author other than Dr. Boehm or
an employee of Biosym appears in the following reference:

"Rational Modification of Human Synovial Fluid Phospholipase A2
Inhibitors", M.T. Pisabarro, A.R. Ortiz, A. Palomer, F. Cabre,
L. Garcia, R.C. Wade, F. Gago, D. Mauleon, and G. Carganico,
J. Med. Chem., Volume 37, pp. 337-341 (1994).

In reading the above reference, one finds that Ludi was used to
help design "Compound 3 (LM-1228)".  Near the end of the article,
it is stated that: "Compound 3 (LM-1228) is one of the most potent
HSF-PLA2 inhibitors described so far, and represents a new and
encouraging lead compound."

While there are now many publications and examples of using de
Novo design software programs such as Ludi in drug discovery
problems, I am not aware of a published application in which the
de Novo design program was used by someone other than the original
author(s).  I would welcome hearing of additional examples that
cite usages of de Novo design software from people other than
the original developers.

Regards,

Marvin Waldman, Ph.D.
Director, Rational Drug Design
Biosym Technologies, Inc.
e-mail: [email-masked]