Docking and 3D-QSAR Studies of Hydrazone and Triazole Derivatives for Selective Inhibition of GRK2 over ROCK2

Introduction: G protein-coupled receptor kinase 2 (GRK2) is known to be implicated in heart failure, and therefore serves as an important drug target. GRK2 belongs to the protein kinase A, G, and C family and shares high sequence similarity with its closely related protein, the Rhoassociated coiled-coil protein kinase 2 (ROCK2). Therefore, selective inhibition of GRK2 over ROCK2 is considered crucial for heart failure therapy. Objective: To understand the structural factors for enhancing the inhibitory activity for GRK2 and selectivity over ROCK2, we analyzed and compared molecular interactions using the same set of ligands against both receptors. Methods: We have performed molecular docking and three-dimensional quantitative structure activity relationship (3D-QSAR) studies on a series of hydrazone and triazole derivatives. Results: The presence of hydrophobic substituents at the triazole ring, electronegative substituents between the pyridine and triazole ring and hydrophobic substituents near the benzene ring increases the activity of both kinases. Whereas, having non-bulky substituents near the triazole ring, bulky and hydrophobic substations at the benzene ring and electronegative and H-bond acceptor substituents at the triazole ring showed a higher inhibitory preference for GRK2 over ROCK2. Conclusion: The outcome of this study may be used in the future development of potent GRK2 inhibitors having ROCK2 selectivity.