From:	snell.chris ^at^ frccgate.sandoz.com
Date:	Mon, 26 Jun 95 08:27:01 -0400
Subject:	Re: CCL:Quantitative assessment of novel ligands

     In response to your question - 'what molecular parameters can be
     generated to convince an organic chemist to synthesise a molecule you
     have designed?'
     
     Before embarking on this process you should also view the question
     from the organic chemists point of view.  He will be considering your
     compound and prioritising it with other compounds he is already
     synthesising and will probably make this assessment based on
     
     i)  synthesisability (a major problem with de novo designed ligands)
     
     ii) the state of the project (is it early days and leads are scarce,
     or is it towards the end of the project when fine tuning is the
     focus?)
     
     iii) how far is the structure away from the known SAR
     
     iv) in the light of ii and iii what are the chances of success and are
     the risks worth taking.
     
     There are probably other questions, but I doubt whether any other
     parameters will make a great difference to your ability to persuade a
     busy organic chemist to synthesise your compounds.  Presumably you are
     convinced that the molecules you have designed are worth making,
     therefore your best approach is to present your argument based on how
     you have designed the molecules, but most important of all, you should
     have your chemist collaborators on board at an early stage in the
     modelling and involve them as much as possible in the process.
     
     Along with the basic tenet of modelling:
     
     'No modelling without experimentation' (A. Vintner)
     
     we should possibly add:
     
     'No synthesis without dialog' ?!
     
     If you are not convinced yourself that these molecules are worth
     making and that their synthesis will answer this question, then you
     need  to get into activity prediction, i.e. QSAR using MOPAC generated
     parameters, principal component analysis etc, or using Comfa (Tripos).
     These are not trivial exercises but do give a prediction that may help
     to decide whether the molecules are worth synthesising.
     
     Good luck anyway!
     
     Chris Snell
     Molecular Modelling and Computational Chemistry
     Sandoz Institute for Medical Research
     5 Gower Place London WC1E 6BN
     
     E-Mail  snell $#at#$ sandoz.com
     Tel     0171-333-2165
     Fax     0171-387-4116
     
     


______________________________ Reply Separator _________________________________
Subject: CCL:Quantitative assessment of novel ligands
Author:  M.DOOLEY -x- at -x- MAILBOX.UQ.OZ.AU -x- at -x- UMC -x- at -x- HANNET at
DECPostmaster
Date:    25/06/95 21:21


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.
     
Michael Dooley Ph.D.
Centre for Drug Design and Development
University of Queensland
     
     
     
     
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