In Silico-QSAR Modelling of Predicted Rho Kinase Inhibitors Against Cardio Vascular Diseases

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Author(s): Sarvesh Paliwal, Swapnil Sharma, Seema Kesar*, Pooja Mishra, Monika Chauhan, Richa Arya, Kirtika Madan, Shagufta Khan.

Journal Name: Current Computer-Aided Drug Design

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Introduction: Rho-kinase is an essential downstream target of GTP-binding protein RhoA, and plays a crucial role in the calcium-sensitization pathway. Rho-kinase pathway is critically involved in phosphorylation state of myosin light chain, leading to increased contraction of smooth muscles. Inhibition of this pathway has turned out to be a promising target for several indications such as cardiovascular diseases, glaucoma and inflammatory diseases.

Methods: The present work focuses on a division-based 2D quantitative structure-activity relationship (QSAR) analysis along with a docking study to predict structural features that may be essential for the enhancement of selectivity and potency of the target compounds. Furthermore, a set of indoles and azaindoles were also projected based on the regression equation as novel developments. Molecular docking was applied for exploring the binding sites of the newly predicted set of compounds with the receptor.

Results: Results of the docked conformations suggested that introduction of non-bulky and substituted groups in the hinge region of ROCK-II ATP binding pocket would improve the activity by decreasing the bulkiness or length of the compounds. Further, ADME studies were performed to ascertain the novelty and drug-like properties of the designed molecules, respectively.

Keywords: Rho kinase (ROCK) inhibitors, Quantitative structure-activity relationship (QSAR), Molecular modelling, ADME studies,

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(E-pub Ahead of Print)
DOI: 10.2174/1573409915666190307163437
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