BIOPHYSICAL THEORY AND MODELING |
The structural determinants of macrolide-actin binding: in silico insights
James L Melville 1, Iain H Moal 1, Charles Baker-Glenn 1, Peter E Shaw 1, Gerald Pattenden 1 and Jonathan D Hirst 1*
1 University of Nottingham
* To whom correspondence should be addressed. E-mail: jonathan.hirst{at}nottingham.ac.uk.
Submitted on December 22, 2006
Revised on January 26, 2007
Accepted on 6 February 2007
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Abstract |
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By the use of X-ray structures and flexible docking we have developed the first in silico ligand-based view of the structural determinants of the binding of small molecule mimics of gelsolin, natural products bound to actin. Our technique highlights those residues on the actin binding site forming important hydrophobic and hydrogen bonding interactions with the ligands. Significantly, through the flexible docking of toxin fragments, we have also identified potential residues on the actin binding site that have yet to be exploited. Guided by these observations, we have demonstrated that kabiramide C can be modified to produce a structure with a predicted binding energy increased by 20%, while the molecular weight is reduced by 20%, clearly indicating the potential for future elaboration of structures targeting this important component of the cytoskeleton.
Key Words:
actin, docking, macrolides, natural products, toxins
