ArticleScientific reports2019
Computational study of paroxetine-like inhibitors reveals new molecular insight to inhibit GRK2 with selectivity over ROCK1.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 32 citations in OpenAlex.
- Revealing GRK5 Activation Features by Interpretable Machine Learning and Molecular Dynamics Simulation.International journal of molecular sciences · 2026Article
- Canonical or non-canonical, all aspects of G protein-coupled receptor kinase 2 in heart failure.Acta physiologica (Oxford, England) · 2025Review
- Generating Potential RET-Specific Inhibitors Using a Novel LSTM Encoder-Decoder Model.International journal of molecular sciences · 2024Article
- A Workflow Combining Machine Learning with Molecular Simulations Uncovers Potential Dual-Target Inhibitors against BTK and JAK3.Molecules (Basel, Switzerland) · 2023Article
- Theoretical Studies on Selectivity of HPK1/JAK1 Inhibitors by Molecular Dynamics Simulations and Free Energy Calculations.International journal of molecular sciences · 2023Article
- Computer aided designing of novel pyrrolopyridine derivatives as JAK1 inhibitors.Scientific reports · 2021Article
- Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2.International journal of molecular sciences · 2021Article
- Paroxetine-Overview of the Molecular Mechanisms of Action.International journal of molecular sciences · 2021Review
- Molecular Modelling Studies on Pyrazole Derivatives for the Design of Potent Rearranged during Transfection Kinase Inhibitors.Molecules (Basel, Switzerland) · 2021Article
- Article
- Molecular Modeling Study of c-KIT/PDGFRα Dual Inhibitors for the Treatment of Gastrointestinal Stromal Tumors.International journal of molecular sciences · 2020Article
- Rational approach toward COVID-19 main protease inhibitors via molecular docking, molecular dynamics simulation and free energy calculation.Scientific reports · 2020Article
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Authors and funding
3 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
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.
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