In Silico Exploration Of Indole Derivatives As Rho Kinase Inhibitors

Protein kinase (PKs) are located in the entire human body, and play very important roles in life process. As a member of the protein kinase family, rho associated kinase (ROCK) is one of the most important targets for many diseases. ROCK participate in a series of cells function, such as shrinkage, adhesion, migration and proliferation, which is the target for treatment of cardiovascular disease, neurological disorders and cancer. Nowadays, the development of ROCK inhibitors has become a new research hot topic. And the new ROCK inhibitors will play a positive role for the treatment of many diseases. Based on computational biology,61 ROCK promising inhibitors were analyzed through 3D-QSAR models to unveil the relationship between the molecular structure and bioactivity via a series of approaches of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) and molecular docking.Based on the ligand-based alignment, an optimal CoMSIA model (SH) was obtained with good predictive power of Q2= 0.509, R2ncv= 0.987, SEE=0.131, F=287.999 and R2pred= 0.837. The 3D contour maps suggested that the compounds substituted on special position with bulky hydrophobic or hydrophilic groups can enhance the biological activity. For example, adding bulky group at template molecule 26 from position 17 to 25 can increase antagonistic activity; hydrophobic features at region 5,17,18,25 and hydrophilic features at region 19 are favorable. Furthermore, the docking analysis showed that Glu170> Met172 and Asp232 which formed three H-bonds are crucial for ROCK receptor. The present work provides useful guidelines for future structural modifications of this class of compounds, which would assist the development of superior ROCK inhibitors.