Products Cited in Publications Worldwide Drug Repurposing by Virtual Screening: Identification of New Already Approved ROCK Inhibitors as Promising Drugs to Target Neurodegeneration

Drug Repurposing by Virtual Screening: Identification of New Already Approved ROCK Inhibitors as Promising Drugs to Target Neurodegeneration

Silva Franco, Lucas; Rodrigues, Daniel Alencar; Baumart, Gabriela Joras; de Jesus, Bárbara da Silva Mascarenhas; Gomes, Flávia Carvalho Alcantara; Lima, Lídia Moreira; Fraga, Carlos Alberto Manssour; Pinheiro, Pedro de Sena Murteira

DOI:

Abstract

kinases are key players in neurodegenerative diseases such as Alzheimer’s disease (AD), making them attractive therapeutic targets. In this study, we developed a pharmacophoric map of inhibitors and highlighted the key affinity sites in ROCK1/2 through molecular modeling. Virtual screening led to the identification of six approved drugs as inhibitors: (36), (37), (38), (39), (40), and (41). (36) (hROCK1 IC50 = 0.025 μM; hROCK2 IC50 = 0.007 μM) and (37) (hROCK1 IC50 = 0.019 μM; hROCK2 IC50 = 0.011 μM) showed the highest potency, while (39) displayed 15-fold selectivity for ROCK2 over ROCK1. Molecular dynamics revealed that (36) forms stable bidentate hydrogen bonds with the hinge region and has selectivity across the AGC kinase family. Biological assays confirmed ruxolitinib’s (36) safety in neuronal and glial cells and its ability to reduce C3 immunolabeling, a glial inflammation marker, in LPS-treated astrocytes. These findings not only highlight (36) as a promising candidate for AD but also provide a structural basis for designing novel dual JAK-ROCK inhibitors and pave the way for further in vitro and in vivo studies. Moreover, the validated pharmacophoric map for inhibition highlights the identification of an affinity pocket that can be useful for the design of new inhibitors.

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