Actin-related protein 2/3 (Arp2/3) complex is a seven subunit ATP-ase that is a key actin cytoskeleton regulator with roles in bacterial pathogenesis and motility of cancer cells. Arp2/3 binds to existing actin filaments and nucleates new filament growth. The biological role of the Arp2/3 complex late in development or in adult stages is undiscovered owing to the lack of potent and reversible Arp2/3 inhibitors. Potent, reversible small molecule inhibitors have the potential to become powerful tools to study the Arp2/3 complex in vivo. Herein, we describe a virtual screening experiment applied to a previously-described allosteric pocket of the Arp2/3 complex, which was employed to discover novel, potent inhibitors of this protein. By carefully post-processing top-scoring ligands using the ChemBioServer (http://bioserver-3.bioacademy.gr/Bioserver/ChemBioServer/), compounds were purchased and assayed. Several low micromolar inhibitors of the complex were identified. Subsequent visualization of the poses of the ligands that were identified as active in the binding site of the protein, unveiled a new pocket at the interface of the Arp2 and Arp3 subunits that can be exploited for additional structure-based optimization for the discovered and existing Arp2/3 inhibitors. Optimization efforts in this direction based on free energy perturbation (FEP) calculations are described.

Discovery and optimization of novel Arp2/3 complex inhibitors via computer-aided drug design

248th National Meeting (2014)

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