Molecular docking and pharmacophore model studies of Rho kinase inhibitors

Wang, Donghua; Qu, Wanlu; Shi, Liuqing; Wei, Jing

doi:10.1080/08927022.2011.554548

Cited by 5 publications

(2 citation statements)

References 72 publications

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“…During in silico studies, the developed pharmacophore exhibited the importance of HBA, HY, and HBD features in eliciting the RhoA/ROCK inhibitory activity. Earlier study reported 10 that the pharmacophore model having 1HBA and 2HY chemical features have the ability to interact and inhibit RhoA/ROCK. In contrast to this, we observed that in addition to HBA and HY, one HBD if present can substantiate the inhibitory activity by interacting within the hinge region of ATP binding site of the enzyme.…”

Section: ■ Pharmacophore Model Validationmentioning

confidence: 99%

Identification of Novel Rho-Kinase-II Inhibitors with Vasodilatory Activity

Kesar

Paliwal

Mishra

et al. 2020

ACS Med. Chem. Lett.

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Small GTPase protein Rho-kinase (ROCK) plays an important role in the pathogenesis of hypertension. Inhibition of ROCK II brings about the biochemical changes leading to vascular smooth muscles relaxation, finally resulting into potent antihypertensive activity. In the quest for potent ROCK-II inhibitors, a ligand-based pharmacophore containing four essential chemical features, namely two hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD), and one hydrophobe (HY), was developed and rigorously validated. The pharmacophore was used for virtual screening, and hits retrieved from the National Cancer Institute (NCI) database were sorted on the basis of fit value, estimate value, and Lipinski's violation. Potential feature interaction of hits was also observed during docking studies with the amino acids present in the active site of Rho-kinase. Based on the above screening, three hits (NSC 2488, NSC 2888, and NSC 4231) were chosen and subjected to in vitro Rho-kinase enzyme-based assay, followed by ex vivo rat aortic vasodilatory assay. All three compounds showed good biological activity as predicted by the model and confirmed by the docking studies.

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Section: ■ Pharmacophore Model Validationmentioning

confidence: 99%

Identification of Novel Rho-Kinase-II Inhibitors with Vasodilatory Activity

Kesar

Paliwal

Mishra

et al. 2020

ACS Med. Chem. Lett.

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“…A three-dimensional (3D) structure library containing 1,792 compounds was established for the virtual screen. Structures of these compounds were generated using a two-dimensional (2D)/3D editor-sketcher and were minimized to a local energy minimum using the CHARMm-like force field implemented within with Catalyst 4.11 software (8). The 3D structure of TRAF6 (residues 50-159, RING and zinc finger domains) was retrieved from the Protein Data Bank as the docking receptor (http://www.rcsb.org/pdb; accession no.…”

Section: Introductionmentioning

confidence: 99%

Suppression of tumor cell proliferation by quinine via the inhibition of the tumor necrosis factor receptor-associated factor 6-AKT interaction

Liu

et al. 2016

Molecular Medicine Reports

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Protein kinase B (AKT), is a pivotal component of pathways associated with cell survival, metabolism, invasion and metastasis. AKT mediates anti‑apoptotic and proliferative signaling in response to essential cytokines. Tumor necrosis factor receptor‑associated factor (TRAF)6, an E3 ubiquitin ligase, has been shown to ubiquitylate, as well as activate AKT. The present study used computational methods to determine the relevant amino acid residues at the binding site of TRAF6 and selected small molecules, which may bind to TRAF6. An ex vivo assay was performed to determine their antitumor activities and the possible mechanism of action. Quinine, a natural alkaloid that is well‑known for its therapeutic treatment of malaria, exhibited a distinct antiproliferative and pro‑apoptotic effect in HeLa and A549 tumor cell lines via the inhibition of the antiapoptotic protein, B‑cell lymphoma (BCL)‑2, and activation of the pro‑apoptotic factor, BCL‑2‑associated X protein. Quinine inhibited the lipopolysaccharide (LPS)‑induced activation of AKT by inhibiting its phosphorylation at Thr‑308 and Ser‑473, and reversing LPS‑induced proliferation. These results suggested that the inhibition of AKT activation via targeting of TRAF6 with quinine may be a viable anticancer therapeutic approach and a successful example of the alternative use of the original therapeutic properties of this well‑known natural product.

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