Mechanism of Isoquinoline Derivatives Inhibiting ROCK1 Protein with 3D-QSAR, Induced Fit Docking and Virtual Screening

Published: 4 July 2023| Version 1 | DOI: 10.17632/hvbctgp8rz.1
Qi-Xuan Xu


Rho-associated coiled-coil containing kinases (ROCKs) have been studied as downstream effectors of small guanosine triphosphatases. A series of isoquino-line derivatives have been extensively studied as ROCK1 inhibitors (RKIs) in recent years. To better understand its pharmacological properties and to explore its potential inhibitors, a series of RKIs derived from isoquinoline derivatives were investigated by using three-dimensional quantitative structure-activity rela-tionship (3D-QSAR) models, induced fit docking, and virtual screening. The comparative Molecular Field Analysis (CoMFA) model (q2 = 0.609, R2 = 0.991, ONC = 6, and r2pred = 0.973) and the best Comparative Molecular Similarity In-dices Analysis (CoMSIA) model (q2= 0.712, R2 = 0.998, ONC = 7, and r2pred = 0.890) exhibited reliable predictability with satisfactory validation parameters. The mechanism of action of isoquinoline-based RKIs was investigated using methods with higher docking precision, such as Induced Fit Docking (IFD), along with Structural Interaction Fingerprints (SIFT) and Binding Pose Metady-namics (BPMD) simulations. Screening of Enamine's HLL-460 compound li-brary using the PRRR_2 pharmacophore resulted in thousands of compounds matching the profile. Three final compounds (DS01, DS02, and DS03) were ob-tained through Glide docking at different precision levels. These compounds were evaluated for their drug-forming properties using QikProp and Swis-sADME, demonstrating their potential as novel and effective RKIs. Molecular dynamics simulations and activity assays also confirmed the activity of the screened molecules. This study provides validated drug development strategies and important insights for designing RKIs.



Nanjing University of Chinese Medicine


Quantitative Structure-Activity Relationship, Screening