Design, Synthesis and Biological Evaluation of Benzothiazoles as Highly Potent ROCK Inhibitors Through Molecular Docking and Free Energy Calculations

Rock has been considered to provide a pharmacological strategy for preventing and treating multiple sclerosis, pulmonary hypertension, glaucoma, cardiovascular disease, erectile dysfunction and cancer. With 3 previously reported and benzothiazole. based ROCK inhibitors(1-3) as the research targets, the structure. activity relationship (SAR) was preliminary revealed from amino acid level by molecular docking after obtaining the stable ROCK2-ligand complexes in the binding pocket through molecular dynamic simulations. Then MM/GBSA free energy calculations of compounds 1-3 showed that there was good correlation between binding affinity(Delta G(bind)) and inhibitory activities, and van der Waals interaction(Delta G(VDW)) contributing to Delta G(bind) most. And the key amino acids with outstanding contribution for high inhibition were obtained through free energy analysis. Finally, 3 series of benzothiazoles(D1-D10) were designed according to the results of molecular docking and free energy calculations. In the biological evaluation, compounds D1-D10 exhibited 2-105 nmol/L IC50 values against ROCK2 and 11-288 nmol/L IC50 values against ROCK1.. Compounds D3-D5 exhibited higher metabolic stability than reported compounds 1 and 3 in human liver microsome studies. This work not only gave theoretical guidance for the design of highly potent ROCK, but also offered a series of highly active ROCK inhibitors with intellectual property right for fundamental research and application of ROCK.