Stepwise high-throughput virtual screening of Rho kinase inhibitors from natural product library and potential therapeutics for pulmonary hypertension

Abstract

(2015) Stepwise high-throughput virtual screening of Rho kinase inhibitors from natural product library and potential therapeutics for pulmonary hypertension, Pharmaceutical Biology, 53:8, 1201-1206, DOI: 10.3109/13880209.2014 ORIGINAL ARTICLEStepwise high-throughput virtual screening of Rho kinase inhibitors from natural product library and potential therapeutics for pulmonary hypertension Hao Su, Ji Yan, Jian Xu, Xi-Zhen Fan, Xian-Lin Sun, and Kang-Yu Chen Department of Cardiology, Anhui Provincial Hospital, Hefei, China Abstract Context: Pulmonary hypertension (PH) is a devastating disease characterized by progressive elevation of pulmonary arterial pressure and vascular resistance due to pulmonary vasoconstriction and vessel remodeling. The activation of RhoA/Rho-kinase (ROCK) pathway plays a central role in the pathologic progression of PH and thus the Rho kinase, an essential effector of the ROCK pathway, is considered as a potential therapeutic target to attenuate PH. Objective: In the current study, a synthetic pipeline is used to discover new potent Rho inhibitors from various natural products. Materials and methods: In the pipeline, the stepwise high-throughput virtual screening, quantitative structure-activity relationship (QSAR)-based rescoring, and kinase assay were integrated. The screening was performed against a structurally diverse, drug-like natural product library, from which six identified compounds were tested to determine their inhibitory potencies agonist Rho by using a standard kinase assay protocol. Results: With this scheme, we successfully identified two potent Rho inhibitors, namely phloretin and baicalein, with activity values of IC 50 ¼ 0.22 and 0.95 mM, respectively. Discussion and conclusion: Structural examination suggested that complicated networks of nonbonded interactions such as hydrogen bonding, hydrophobic forces, and van der Waals contacts across the complex interfaces of Rho kinase are formed with the screened compounds.

Recent advances in the development of Rho kinase inhibitors (2015–2021)

“…Several potent and selective ROCK inhibitors identified by modern drug discovery techniques are undergoing clinical trials for the treatment of multiple diseases 109,110 . Nevertheless, the structural diversity between these synthetic ROCK inhibitors is an issue which can hopefully be overcome with the discovery of natural products with moderate to potent ROCK inhibitory action 111,112 . These newly identified compounds may provide new leads for the development of improved, safer, and more effective ROCK inhibitors for the treatment of cancers.…”

Therapeutic targeting of oncogenic transcription factors by natural products in eye cancer

“…Lanostane triterpenoids were found to have the most potent activities. In another study, Su et al virtually screened a natural product library and found phloretin and baicalein to inhibit Rho-kinase [81]. Phloretin is a dihydrochalcone found in apple and pears [82].…”