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The Structural Determinants of Macrolide-Actin Binding: In Silico Insights

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

^* School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom; and Centre for Biochemistry and Cell Biology, School of Biomedical Sciences, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom

Correspondence: Address reprint requests to J. D. Hirst, E-mail: jonathan.hirst{at}nottingham.ac.uk.

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.