Designing of the N-ethyl-4-(pyridin-4-yl)benzamide based potent ROCK1 inhibitors using docking, molecular dynamics,...

Area of Science:

• Medicinal Chemistry
• Computational Biology
• Pharmacology

Background:

• Rho-associated kinase-1 (ROCK1) is implicated in cardiovascular diseases, malignancy, and neurological disorders.
• ROCK1 hyperactivity contributes to smooth muscle cell contraction, relevant to vascular system pathologies.
• ROCK1 inhibition presents a promising therapeutic strategy for cardiovascular conditions.

Purpose of the Study:

• To investigate N-ethyl-4-(pyridin-4-yl)benzamide derivatives as potential ROCK1 inhibitors.
• To establish structure-activity relationships (SAR) for designing more potent ROCK1 inhibitors.
• To provide insights for developing novel therapeutic agents targeting ROCK1.

Main Methods:

• Employed molecular modeling techniques including docking and molecular dynamics (MD) to analyze compound-ROCK1 interactions.
• Utilized 3-Dimensional quantitative structure-activity relationship (3D-QSAR) methods, specifically Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA).
• Designed and evaluated new compounds based on SAR insights, followed by ADME/Tox and SA score predictions.

Main Results:

• Docking and MD simulations identified critical interactions and binding affinities between ROCK1 and tested inhibitors.
• CoMFA and CoMSIA models demonstrated good predictive capabilities (q²=0.774, q²=0.676 respectively) and revealed key substitution patterns.
• Seven newly designed compounds exhibited enhanced predictive activity (pIC50), with further analyses supporting their potential.

Conclusions:

• The integrated approach of docking, MD, and 3D-QSAR effectively guided the modification of existing molecules.
• The study successfully identified promising novel ROCK1 inhibitors with potential therapeutic applications.
• Findings offer valuable insights for the future development of more potent ROCK1-targeting drugs.