Novel inhibitors of Rho-kinase mediated neuroinflammatory pathways and their potential application in recovery of injured spinal cord.

Spinal cord injury (SCI) involves damage to any part of the spinal cord which results in temporary or permanent changes in its function. Spinal cord secondary injury activates Rho-associated protein kinase 2 (ROCK2), which is involved in neuroinflammation and cell death by mediating secretion of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β), interleukin-2 (IL-2), and CXC chemokines. Here we evaluated potential inhibitors of ROCK2, Caspase-1, and TNF-α from Cissus quadrangularis derived natural compounds and compared them with structural analogues of quadrangularin by molecular docking, followed by correlation using molecular dynamic simulations studies. The results clearly demonstrate that the naturally derived compounds, quadrangularin and luteolin potentially inhibit ROCK2 and Caspase-1 with high binding affinity, and showed stable conformation throughout simulation trajectory period. Interestingly, quadrangularin and its structural analogues demonstrate effective binding affinity against ROCK2, caspase-1, and TNF-α when compared to their respective known inhibitors. From our studies, we can infer that natural compounds derived from C. quadrangularis are potentially capable of inhibitory activity against ROCK2, Caspase-1, and TNF-α. These findings could help in identifying novel therapeutic drugs targeting SCI.Communicated by Ramaswamy H. Sarma.