Identification of Withanolide G as a Potential Inhibitor of Rho-associated Kinase-2 Catalytic Domain to Confer Neuroprotection in Ischemic Stroke

Background: Cerebral stroke is one of the leading causes of death and disability in a large number of patients globally. Brain damage in ischemic stroke is led by a complex cascade of events. The Rho-associated kinase-2 (ROCK2) has a significant role in cerebral vasospasm, vascular remodeling, and inflammation. It is activated in cerebral ischemia and its inhibition leads to a neuroprotective effect. Objective: The present study is designed to identify potential inhibitors of ROCK2 using a molecular docking approach. Methods: We docked phytochemicals of Withania somnifera (WS) into the catalytic site of ROCK2 and compared results with inhibitor Y-27632. ADME and drug-likeness properties of WS phytochemicals were also analyzed. Results: Results suggest that 11 phytochemicals exhibited higher binding affinity toward the ROCK2 catalytic domain compared to the Y-27632 inhibitor. Among these phytochemicals, Withanolide G formed H-bonding and established hydrophobic contacts with key catalytic domain residues of ROCK2. Conclusion: Our findings suggest that Withanolide G has the potential to inhibit the action of ROCK2 and can be developed as a neurotherapeutic agent to combat cerebral ischemic insult.