Theoretical Research Of Rho Kinase Inhibitors

Rho-associated coiled-coil protein kinase(ROCK),a serine/threonine protein kinase,is one of the downstream effectors of the small GTPase RhoA and belongs to the AGC family.To date,Rock inhibitors have been considered to provide a pharmacological strategy for preventing and treating multiple sclerosis,pulmonary hypertension,glaucoma,cardiovascular disease,erectile dysfunction,and cancer.We abundantly screened comparative molecular field analysis(CoMFA)and comparative similarity indices analysis(CoMSIA)models with34 chroman-benzoazole based ROCK inhibitors as the database.The regression analysis was carried out using the partial least squares(PLS)method and the final models were selected according to the statistical parameters.According to steric field,electrostatic field,hydrophobic field,hydrogen bond donor and acceptor field contribution,hydrophobic field was the major contribution,and the three-dimensional maps analysis of five fields suggested that the introduction of hydrophobic groups in the chroman region was favored for ROCK2 inhibitory activity.With three different activity benzothiazole derivatives in the model as the research targets,three kinds of inhibitor-receptor complex was obtain through docking and molecular dynamics simulation,by comparing the binding modes of the inhibitors in the protein pocket,we obtain the preliminary explanation of their structure-activity relationship(SAR).Then the results of the MM-GB/SA free energy calculations suggested that stable hydrogen-bonding interactions between pyrazole rings and Glue170 and Met172,hydrophobic interactions between Gly101,Ala102,Phe103,Glu105,Val106,Leu221,Phe136 and the chroman ring were essential for the novel ROCKs inhibitors,which was in agreement with the results of 3D-QSAR model.Finally,three series of benzothiazole-based inhibitors(D1-D10)were designed according to the results of 3D-QSAR,molecular docking and free energy calculations.And this work gave theoretical guidance for the design of highly potent ROCK.In study of the selectivity inhibitors between ROCK1 and ROCK2 isoforms.Firstly,through molecular docking and molecular dynamics simulations of the highly selective inhibitor KD025,we speculated that the reason for the high selectivity of KD025 is mainly due to the different hydrophobic interactions among different subtypes of ROCK protein binding pockets.The results of binding energy calculation study are consistent with their experimental activities,and further energy decomposition shows the residues around the P-loop(Gly101,Ala102,Phe103 and Gly104)have significant contribution to the selectivityof KD025-ROCK1/2.We expect that these studies will provide more ideas for the design of efficiently selective ROCKs inhibitors.