The structural determinants of macrolide-actin binding: in silico insights.

James L Melville, Iain H Moal, Charles Baker-Glenn, Peter E Shaw, Gerald Pattenden, Jonathan D Hirst

School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom.

Biophysical journal 2007 Jun 1

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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 mass is reduced by 20%, clearly indicating the potential for future elaboration of structures targeting this important component of the cytoskeleton.

Citation

James L Melville, Iain H Moal, Charles Baker-Glenn, Peter E Shaw, Gerald Pattenden, Jonathan D Hirst. The structural determinants of macrolide-actin binding: in silico insights. Biophysical journal. 2007 Jun 1;92(11):3862-7