The Search for Allosteric Inhibitors for Rho Associated Kinases
Rho Kinases or ROCKs are multifunctional kinases involved in cell migration, neurite outgrowth, and smooth-muscle migration. ROCK I and ROCK II have been identified as ROCK isoforms. These isoforms share 92% identity in kinase domains and their mRNA’s can be found in mouse and rat tissues. The transcripts for ROCKs have high expression levels in the heart, muscle and brain. ROCK has several substrates implicated in cell migration and inhibitors can modulate cell migration and tissue remodeling. ROCK-1 (-/-) null mice do not develop fibrosis and cardiac dysfunction characteristic for ischaemic/reperfusion cardiomyopathy (I/RC); providing a strong rational to pursue drug discovery. During metastasis and tumour-cell invasion, its been discovered that ROCK increases cell migration. Y-27632 and fasudil are ROCK inhibitors can be used to inhibit ROCKs effects on cell migration and reduce tumour-cell dissemination. However Y-27632 and fasudil have off target binding to other kinase family members and severe side effects. I have begun a computation screen of small chemical molecules that might bind ROCKs in an allosteric and specific mechanism looking for effective and save drug leads. This rational approach uses molecular modeling and docking to find compounds that bind near the activation loop or other allosteric pockets.