Rational Design of Rho GTPase-Targeting Inhibitors

  • Xun ShangEmail author
  • Yi Zheng
Part of the Methods in Molecular Biology book series (MIMB, volume 928)


Rho GTPases have been implicated in diverse cellular functions and are potential therapeutic targets in inflammation, cancer, and neurologic diseases. Virtual screening of compounds that fit into surface grooves of RhoA known to be critical for guanine nucleotide exchange factor (GEF) interaction produced chemical candidates with minimized docking energy. Subsequent screening for inhibitory activity of RhoA binding to the Rho-GEF, LARG, identified a Rho-specific inhibitor as a lead compound capable of blocking RhoA–LARG interaction and RhoA activation by LARG specifically and dose dependently. A microscale thermophoresis analysis was applied to directly quantify the binding interaction of the lead inhibitor with RhoA target. The lead inhibitor highlights the principle that rational targeting of subfamily members of Rho GTPases is feasible and potentially useful in future drug design effort.

Key words

Rho GTPases RhoA Signaling Small molecule Inhibitor Rational drug design Targeting 


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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Division of Experimental Hematology and Cancer Biology, Children’s Hospital Medical CenterUniversity of CincinnatiCincinnatiUSA
  2. 2.Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical CenterUniversity of CincinnatiCincinnatiUSA

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