Discovery of novel CDK8 inhibitors using multiple crystal structures in docking-based virtual screening

Wang, Taijin; Yang, Zhuang; Zhang, Yongguang; Yan, Wei; Wang, Fang; He, Libang; Zhou, Yuanyuan; Chen, Lijuan

doi:10.1016/j.ejmech.2017.02.020

Cited by 28 publications

(13 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The results are presented as total energy values for the Moldock Score ligand-receptor interaction. For proteins bearing ligands, redocking of the complexed ligands together with the respective proteins was carried out using Root Mean Square Deviation (RMSD) values [70][71][72][73].…”

Section: Molecular Dockingmentioning

confidence: 99%

Docking Prediction, Antifungal Activity, Anti-Biofilm Effects on Candida spp., and Toxicity against Human Cells of Cinnamaldehyde

et al. 2020

View full text Add to dashboard Cite

Objective: This study evaluated the antifungal activity of cinnamaldehyde on Candida spp. In vitro and in situ assays were carried out to test cinnamaldehyde for its anti-Candida effects, antibiofilm activity, effects on fungal micromorphology, antioxidant activity, and toxicity on keratinocytes and human erythrocytes. Statistical analysis was performed considering α = 5%. Results: The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of cinnamaldehyde ranged from 18.91 μM to 37.83 μM. MIC values did not change in the presence of 0.8 M sorbitol, whereas an 8-fold increase was observed in the presence of ergosterol, suggesting that cinnamaldehyde may act on the cell membrane, which was subsequently confirmed by docking analysis. The action of cinnamaldehyde likely includes binding to enzymes involved in the formation of the cytoplasmic membrane in yeast cells. Cinnamaldehyde-treated microcultures showed impaired cellular development, with an expression of rare pseudo-hyphae and absence of chlamydoconidia. Cinnamaldehyde reduced biofilm adherence by 64.52% to 33.75% (p < 0.0001) at low concentrations (378.3–151.3 µM). Cinnamaldehyde did not show antioxidant properties. Conclusions: Cinnamaldehyde showed fungicidal activity through a mechanism of action likely related to ergosterol complexation; it was non-cytotoxic to keratinocytes and human erythrocytes and showed no antioxidant activity.

show abstract

Section: Molecular Dockingmentioning

confidence: 99%

Docking Prediction, Antifungal Activity, Anti-Biofilm Effects on Candida spp., and Toxicity against Human Cells of Cinnamaldehyde

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The R&D for new type I CDK8 ligands made a significant progress in the past a couple of years and many promising compounds were identified. [18, 19] In 2016 new potent and selective CDK8 ligands with benzylindazole scaffold previously reported as HSP90 ligands were described by Schiemann et al [20] One of the most promising molecules showed an IC50 value against CDK8/CycC of 10 nM. More recently 4,5-dihydrothieno[3’,4’:3,4]benzo[1,2-d] isothiazole derivatives were found to have sub-nanomolar in-vitro potency (IC50: 0.46 nM) against CDK8/CycC and high selectivity.…”

Section: Introductionmentioning

confidence: 99%

Discovery of CDK8/CycC Ligands with a New Virtual Screening Tool

2018

View full text Add to dashboard Cite

Selective inhibition of Cyclin-dependent kinase 8 and cyclin C (CDK8/CycC) has been suggested as a promising strategy for reducing mitogenic signals in cancer cells with reduced toxic effects on normal cells. We developed a novel virtual screening protocol for drug development and applied it to discovering new CDK8/CycC type II ligands, which is likely to achieve long residence time and specificity. We first analyzed binding thermodynamics of 11 published pyrazolourea ligands using molecular dynamics simulations and a free energy calculation method, VM2, and extracted the key binding information to assist virtual screening. The urea moiety was found to be the critical structural contributor of the reference ligands. Starting with the urea moiety we conducted substructure-based searches with our newly developed Superposition and Single-Point Energy Evaluation method, followed by free energy calculations, and singled out three purchasable compounds for bio-assay testing. The ranking from the experimental result is completely consistent with the predicted rankings. A potent drug-like compound has a Kd value of 42.5 nM, which is comparable to the most potent reference ligands and provided a good starting point for further improvement. This study shows that our novel virtual screening protocol is an accurate and efficient tool for drug development.

show abstract

“…The re-docking test is an experimental method to evaluate the reproducibility of a complex structure by docking calculation and it has always been used to evaluate the performance of a docking program [50][51][52]. The docking programs were considered to qualify for virtual screening if the root mean square deviation (RMSD) for the ligand between the docked conformation and the crystallographic conformation was < 2 Å [53,54]. Herein, the TNKS-2 protein bound original ligand XAV939 was re-docked into the binding pocket by DOCK6.5 or Autodock4.2, the RMSD of the ligand between obtained the docked pose.…”

Section: Preparation For Structure-based Virtual Screeningmentioning

confidence: 99%

Discovery of Novel Inhibitor for WNT/β-Catenin Pathway by Tankyrase 1/2 Structure-Based Virtual Screening

Liang

et al. 2020

Molecules

View full text Add to dashboard Cite

Aberrant activation of the WNT/β-catenin signaling pathway is implicated in various types of cancers. Inhibitors targeting the Wnt signaling pathway are intensively studied in the current cancer research field, the outcomes of which remain to be determined. In this study, we have attempted to discover novel potent WNT/β-catenin pathway inhibitors through tankyrase 1/2 structure-based virtual screening. After screening more than 13.4 million compounds through molecular docking, we experimentally verified one compound, LZZ-02, as the most potent inhibitor out of 11 structurally representative top hits. LiCl-induced HEK293 cells containing TOPFlash reporter showed that LZZ-02 inhibited the transcriptional activity of β-catenin with an IC50 of 10 ± 1.2 μM. Mechanistically, LZZ-02 degrades the expression of β-catenin by stabilizing axin 2, thereby diminishing downstream proteins levels, including c-Myc and cyclin D1. LZZ-02 also inhibits the growth of colonic carcinoma cell harboring constitutively active β-catenin. More importantly, LZZ-02 effectively shrinks tumor xenograft derived from colonic cell lines. Our study successfully identified a novel tankyrase 1/2 inhibitor and shed light on a novel strategy for developing inhibitors targeting the WNT/β-catenin signaling axis.

show abstract

Discovery of novel CDK8 inhibitors using multiple crystal structures in docking-based virtual screening

Cited by 28 publications

References 20 publications

Docking Prediction, Antifungal Activity, Anti-Biofilm Effects on Candida spp., and Toxicity against Human Cells of Cinnamaldehyde

Docking Prediction, Antifungal Activity, Anti-Biofilm Effects on Candida spp., and Toxicity against Human Cells of Cinnamaldehyde

Discovery of CDK8/CycC Ligands with a New Virtual Screening Tool

Discovery of Novel Inhibitor for WNT/β-Catenin Pathway by Tankyrase 1/2 Structure-Based Virtual Screening

Contact Info

Product

Resources

About