Subject: Toplogical indices and active sites, Software for binding affinities

From: <[email-masked]>
Date: Tue, 02 Jul 96 08:17:28 +0200

Dear Netters,

to state my question, let me - briefly - give some backgrounds: 
It has been shown that topological indices are well-suited for describing 
similarity/dissimilarity of molecules. If two compounds
have close values of a number of indices, they can be regarded as similar.
The same way correlations with physico-chemical properties are established.
In the beginning, experimental results are known for a number of structures.
By calculating several topological indices for these molecules and performing
some kind of statistical analysis (e.g. regression analysis) a correlation
between the experimental values and the values of the topological indices can be
found.

But often the direction of research is rather for _complementarity_
than for _similarity_. That means that an active site of a pharmacophore is given
and a receptor/inhibitor is desired. I am convinced that topological indices
can also be used for this task of "de novo" design, since many decisive effects
like hydrophobicity or charge distribution can be already modelled. However,
I am not sure how exactly this usage can look like. How can the active site
be analyzed to obtain constraints (or limits) for the values of the topological
indices of the descriptor?

I have already asked this question a number of experts but without substantial
results. A related, but somewhat easier problem is: If I have the topological 
structure of a compound, how can I determine if there is any conformation of
this molecule that matches with a given (i.e. given as 3D) active site? What
kind of software should I use to check the binding affinities (and how)?

These problems have also a strong relationship to combinatorial chemistry
where the quality of library could be evaluated by these means.

I would highly appreciate to receive any help. Maybe we can start a fruitful
discussion. I will summarize the results to the list(s) if there is enough interest.
 
Best regards,

Thomas Wieland               +---------------+
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