3D-Quantitative Structure-Activity Relationship and design of novel Rho- associated protein kinases-1 (ROCK1) inhibitors

Abstract

Rho-associated coiled-coil kinases (ROCKs) are involved in essential cellular functions such as adhesion, contraction, motility, proliferation, and cell survival/apoptosis. Four ROCK inhibitors have already been approved by the FDA and are used to treat glaucoma (ripasudil and netarsudil), cerebral vasospasm (fasudil), and graft-versus-host disease (belumosudil). Recent studies have focused on exploring the role of ROCK kinase inhibitors in cancer treatment and the development of new ROCK inhibitors. The main objective of this study was to identify critical structural features relevant to the inhibition of ROCK1 using a ligand-based 3D-QSAR (3D quantitative structure-activity relationship) method. The 3D-QSAR model for ROCK1 was created and validated using internal and external validation parameters (R2, Q2, R2pred, rm2, r/2m, 𝑟���������𝑚��������� 2̅̅̅ and ∆r2m). The main structural features that correlate with the inhibition of ROCK1 were identified (e.g., heterocycle with hydrogen donor group like nitrogen atom) and further structural modifications of the ROCK1 inhibitors that contribute to increased activity were proposed (removal of the amino group of the oxadiazole, modification of the substituents of the phenyl ring).