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Abstract
The G-protein coupled receptor kinase 2 (GRK2) regulates the desensitization of beta-adrenergic receptors (β-AR), and its overexpression has been implicated in heart failure. Hence, the inhibition of GRK2 is considered to be an important drug target for the treatment of heart failure. Due to the high sequence similarity of GRK2 with the A, G, and C family (AGC family) of kinases, the inhibition of GRK2 also leads to the inhibition of AGC kinases such as Rho-associated coiled-coil kinase 1 (ROCK1). Therefore, unraveling the mechanisms to selectively inhibit GRK2 poses an important challenge. We have performed molecular docking, three dimensional quantitative structure activity relationship (3D-QSAR), molecular dynamics (MD) simulation, and free energy calculations techniques on a series of 53 paroxetine-like compounds to understand the structural properties desirable for enhancing the inhibitory activity for GRK2 with selectivity over ROCK1. The formation of stable hydrogen bond interactions with the residues Phe202 and Lys220 of GRK2 seems to be important for selective inhibition of GRK2. Electropositive substituents at the piperidine ring and electronegative substituents near the amide linker between the benzene ring and pyrazole ring showed a higher inhibitory preference for GRK2 over ROCK1. This study may be used in designing more potent and selective GRK2 inhibitors for therapeutic intervention of heart failure.
Highlights
Heart failure is a condition in which the heart fails to produce sufficient myocardial contraction needed to effectively circulate blood throughout the body
The x-ray crystal structure of Rho-associated coiled-coil containing kinase 1 (ROCK1) (PDB ID 6E9W) in complex with a pyridinylbenzamide derivative reported by Hobson et al.[31] was used for the docking study of compound 11, 17 and 47
We have used molecular docking, molecular dynamics simulation, free energy calculation and 3D-QSAR methods to study a series of 53 paroxetine-like inhibitors to understand the structural properties that drive the inhibitory preference for G-protein coupled receptor kinase 2 (GRK2) over ROCK1
Summary
Heart failure is a condition in which the heart fails to produce sufficient myocardial contraction needed to effectively circulate blood throughout the body. Rho-associated coiled-coil containing kinase (ROCK2) is another member of the AGC kinase family They are known to play an important role in cell migration and invasion, centrosome duplication, cytokinesis, and apoptosis[17]. Waldschmidt et al, have reported a series of paroxetine-like compounds that showed high inhibitory activity for GRK2 and selectivity over other AGC kinases[13,27]. A study of this series of paroxetine-like compounds with the objective to understand the structural factors that drive its potency and selectivity for GRK2 poses an interesting challenge. The contour map results and docking analyses of individual receptors were co-analysed to identify the crucial interactions and structural properties that are important to increase the inhibitory activity for GRK2 and selectivity over ROCK1
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