Subject: electrophilicity -> drug potency?

From: [email-masked] (BRYAN MARTEN)
Date: Fri, 26 Sep 1997 13:40:23 -0400

Dear CCLers,

Has anyone looked at how electronic properties of electrophilic ligands involved
in enzymatic nucleophilic attack are correlated to biological activity?

One can imagine having limited computational resources yet posessing a series of
compounds containg a variety of electron-withdrawing groups near an
electrophilic atom, which gets attacked by a nucleophile in an enzyme, and
attempting to correlate properties of the ligand (possibly only properties
pertaining to the point of attack) with the strength of the bond to the enzyme's
nucleophile and therefore to a piece of the overall in vitro potency of each
ligand.  Contributions to potency from nonbonded interactions and other sources
would be treated separately.

The idea is that, since the nucleophile is always the same and the electrophiles
are the only things changing, can you get away with only computing properties of
the electrophile (which properties?) and still expect get reasonable
correlations to relative bond energies and then hopefully to a piece of their 
relative binding affinities?

A search of the CCL archives reveals that a similar question was posed here
about 2.5 years ago but I'm told no responses were received.

Bryan Marten, PhD
Schering-Plough Research Institute