Design of novel lead molecules against RhoG protein as cancer target – a computational study

Abstract

Cancer is a class of diseases characterized by uncontrolled cell growth. Every year more than 2 million people are affected by the disease. Rho family proteins are actively involved in cytoskeleton regulation. Over-expression of Rho family proteins show oncogenic activity and promote cancer progression. In the present work RhoG protein is considered as novel target of cancer. It is a member of Rho family and Rac subfamily protein, which plays pivotal role in regulation of microtubule formation, cell migration and contributes in cancer progression. In order to understand the binding interaction between RhoG protein and the DH domain of Ephexin-4 protein, the 3D structure of RhoG was evaluated and Molecular Dynamic Simulations was performed to stabilize the structure. The 3D structure of RhoG protein was validated and active site identified using standard computational protocols. Protein–protein docking of RhoG with Ephexin-4 was done to understand binding interactions and the active site structure. Virtual screening was carried out with ligand databases against the active site of RhoG protein. The efficiency of virtual screening is analysed with enrichment factor and area under curve values. The binding free energy of docked complexes was calculated using prime MM-GBSA module. The SASA, FOSA, FISA, PISA and PSA values of ligands were carried out. New ligands with high docking score, glide energy and acceptable ADME properties were prioritized as potential inhibitors of RhoG protein.

Keywords:

• homology modelling
• molecular dynamics
• prime MM-GBSA
• protein–protein docking
• virtual screening

Acknowledgements

The authors TD, BK, RD, AHA, TM and LSP thank The Principal and The Head, Department of Chemistry, University College Science, Osmania University, Hyderabad 500007, for providing facilities to carry out the work. The author TD acknowledges CSIR-SRF (Ref. No: 09/132(0823) 2012 EMR-I) for financial support in pursuing the research work.