Subject: Re: CCL:CoMFA with racemic compunds?

From: Soaring Bear <[email-masked]>
Date: Mon, 10 Feb 1997 10:41:56 -0700 (MST)

>Is it right to use both isomeric structures as CoMFA-input and give them the 
>same activity? 

        The greater the difference of real activity of each 
of the isomers the greater the error will be in prediction.
It just adds another unknown so should be avoided.   Better
to leave those compounds out.

[7m[5m
 ___         _    http://ellington.pharm.arizona.edu/~bear  O-topo-O 
(___        |.)     [email-masked]    5'  :      : .*
 ___)OARING |_)EAR,    UA Pharmacy 404, Tucson 85721     |'*.    .*'| |
 Computer Modeling for Medicinal Chemistry; SAR CAMD     | | *.,* | | |
 Protein/DNA Structural Biology; Cancer Biochemistry    3',DNA helix|.*
 Pharmacognosy, Herbs, Nutrition,  Natural Dentistry       '***'  '** [0m

---

From: [email-masked] (Alan Shusterman)
Date: 10 Feb 97 10:19:40 PST

--- Stefan Schmitt wrote:
The compounds I am analyzing contain one (and for some derivatives two) 
stereogenic center(s). Biological data (IC50) however, is due to 
experimental reasons only availible for racemic mixtures (or diastereomeric 
mixtures in the case of two stereogenic centers).  

My question is now, how to handle this information for a CoMFAnalysis:
Is it right to use both isomeric structures as CoMFA-input and give them the 
same activity? 
It may sound logical but I am not aware if such a proceeding would 
falsify the input for the PLS-analysis.
Alternatively you could use only one isomeric structure, but this would 
not truely reflect the right 3D-demands at the receptor. 
--- end of quoted material ---
This looks like a difficult problem.  You should never assume that the
enantiomers have the same biological activity (occasionally they do, but there
are many many cases where they do not).  It may also be unsafe to assume
similar receptor interactions for each enantiomer, but this will depend on the
structure of the molecule and the mechanism of receptor binding.

Assigning the same activity to both isomers and proceeding with the CoMFA and
PLS analysis will definitely invalidate the results unless the activities of
the isomers are, in fact, similar.

What might be worth a try is to choose one enantiomer in each pair as the more
active molecule and to assign all of the measured activity to this molecule. 
Then, include only this molecule in the CoMFA analysis and discard the other
(until more data becomes available).

Alan Shusterman
Department of Chemistry
Reed College
Portland, OR