Design Of Potency And Selectivity ROCK2 Inhibitors Based On 3D-QSAR, Molecular Docking And Molecular Dynamics

Rho-associated coiled-coil protein kinase (ROCK), a serine/threonine protein kinase, is one of the downstream effectors of the small GTPase Rho A and belongs to the AGC family. Accumulating evidence suggests that ROCK plays essential roles in various cellular functions, such as stress fiber formation, focal adhesion formation, cell aggregation, cell morphology, cytokinesis, cell migration, cell proliferation and apoptosis. Although the potency of ROCK inhibitors was explored by a series of computational studies including molecular docking, 3D-QSAR analysis, molecular dynamics simulation and free energy calculations, but seldom were focused on the selectivity. In fact, most ROCK inhibitors presented non-ignorable cross-activity against closely related AGC kinases. So, It is very important to discover highly potent and selective ROCK inhibitors. In this work, we plan to reveal the structural and chemical properties that favor ROCK inhibition activity and selectivity through molecular modeling based on the data set collected from our previous publications.In the study of ROCK2/PKA:From the data set collected from urea-based ROCK inhibitors,3D-QSAR models including CoMFA activity model, CoMFA selectivity model, CoMSIA activity model, and CoMSIA selectivity model were set up, and the SAR/selectivity were obtained by analyzing the contour maps of CoMFA and CoMSIA models. Molecular docking further demonstrated that H-bonding interaction to residue Asp176 of ROCK2 was the key element for ROCK2/PKA selectivity. A 5 ns MD simulation certified the reliability of docking results. Finally, three new compounds were designed, synthesized, and biologically evaluated, and the potency data obtained from biochemical assays and prediction based on established 3Q-QSAR models were very similar and within the reasonable error range, which indicated that the molecular models were effective for designing highly potent and ROCK2/PKA selective ROCK inhibitors.In the study of ROCK2/1:The compound SLx2119 which have entered clinical studies was docked into ROCK2 and ROCK1 respectively and the predicted biding free energies of ROCK2/1-SLx2119 were obtained on the basis of MM/PBSA. It is expected to find the key residue impact on the selectivity of ROCK2/1 inhibitors.