Subject: receptor flexibility in CADD

From: "Heather A. Carlson" <[email-masked]>
Date: Tue, 02 Nov 1999 02:21:55 -0800

Hello All,

We all know that it is a limitation to use a single protein structure 
to represent a target site on a protein.  However, many of us still use
that approach as there is no accepted way of accommodating the inherent
flexibility of an active site in computer aided drug design.  There are
many means of accommodating ligand flexibility... I am interested in
receptor flexibility.

I've recently developed a method for superimposing multiple protein 
conformations to represent the inherent flexibility of a receptor when
developing a complementary pharmacophore model (an ASAP article is
available through J Phys Chem A: Carlson, Masukawa, McCammon).  The 
only other work I have found that is at all similar is a ligand docking
study by Knegtel, Kuntz, and Oshiro (J Mol Biol 1997, 266, 424-440)
which introduces weighting methods either for the interaction energy 
between a ligand and the receptor or in the description the geometry of
the site.

Does anyone know of methods for accommodating an ensemble of protein 
conformations?  Has anyone tried a similar idea without success or know
of particularly interesting cases where the lack of protein flexibility 
leads to incorrect predictions?

Thank you, 
Heather 
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                   Dr. Heather A. Carlson, Ph.D.
            American Cancer Society Postdoctoral Fellow
      La Jolla Interfaces in Science - BWF Postdoctoral Fellow

UCSD, Dept. of Chemistry and Biochemistry     Phone: (858) 822-1469
9500 Gilman Drive, 4202 Urey Hall               Fax: (858) 534-7042
La Jolla, CA 92093-0365         E-mail: [email-masked]
___________________________________________________________________