Identification of novel CDK2 inhibitors by a multistage virtual screening method based on SVM, pharmacophore and docking model

Liang, Jing-wei; Wang, Mingyang; Wang, Shan; Li, Shilong; Li, Wan-Qiu; Meng, Fan‐hao

doi:10.1080/14756366.2019.1693702

Cited by 20 publications

(16 citation statements)

References 33 publications

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“…LB techniques are generally used in the prefiltering step, as illustrated in different works that have exploited 2D fingerprints [ 81 , 82 ], 3D molecular similarity [ 83 , 84 , 85 ] and pharmacophore models [ 86 , 87 , 88 ]. To enhance the drug-likeness of the compounds, knowledge-based in silico ADMET or pan-assay interference compounds (PAINS; [ 89 ]) filters can also be applied.…”

Section: Sequential Lb and Sb Methodsmentioning

confidence: 99%

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

Vázquez

Lopez

Gibert³

et al. 2020

Molecules

122

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Virtual screening (VS) is an outstanding cornerstone in the drug discovery pipeline. A variety of computational approaches, which are generally classified as ligand-based (LB) and structure-based (SB) techniques, exploit key structural and physicochemical properties of ligands and targets to enable the screening of virtual libraries in the search of active compounds. Though LB and SB methods have found widespread application in the discovery of novel drug-like candidates, their complementary natures have stimulated continued efforts toward the development of hybrid strategies that combine LB and SB techniques, integrating them in a holistic computational framework that exploits the available information of both ligand and target to enhance the success of drug discovery projects. In this review, we analyze the main strategies and concepts that have emerged in the last years for defining hybrid LB + SB computational schemes in VS studies. Particularly, attention is focused on the combination of molecular similarity and docking, illustrating them with selected applications taken from the literature.

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Section: Sequential Lb and Sb Methodsmentioning

confidence: 99%

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

Vázquez

Lopez

Gibert³

et al. 2020

Molecules

122

View full text Add to dashboard Cite

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“…CDK2 is a core regulator of cell cycle through late G1-phase and S-phase. CDK2 is thought to be strongly linked to development of cancer, and accumulating evidence shows that inhibition of CDK2 induces cancer cell apoptosis without normal cell damage [ 34 , 35 ]. TOP2A is a marker of proliferation and chemotherapy resistance in cancer [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

A Network Pharmacology Approach to Explore the Potential Mechanisms of Huangqin-Baishao Herb Pair in Treatment of Cancer

Wang

Liu

2020

Med Sci Monit

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Background: The aim of this study was to identify the bioactive ingredients of Huangqin-Baishao herb pair and to reveal its anti-cancer mechanisms through a pharmacology approach. Material/Methods: Detailed information on compounds in the HQ-BS herb pair was obtained from the Traditional Chinese medicine systems pharmacology (TCMSP) and screened by the criteria of OB ³30% and DL ³0.18. A systematic drug targeting model (SysDT) was used for compound targets prediction, and then the targets were analyzed for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The protein-protein interaction (PPI) network of HQ-BS targets was constructed, after identifying core networks through Cytoscape plugins. Results: We found 47 bioactive compounds of HQ-BS and 107 human-derived targets. A compound target network and a target signal pathway network were constructed and used for topological analysis. Kaempferol, beta-sitosterol, stigmasterol, wogonin, and oroxylin-a were identified as core compounds and pathways in cancer. The calcium signaling pathway, PI3K-Akt signaling pathway, TNF signaling pathway, chemical carcinogenesis, estrogen signaling pathway, proteoglycans in cancer, HIF-1 signaling pathway, thyroid hormone signaling pathway, VEGF signaling pathway, small cell lung cancer, prostate cancer, colorectal cancer, NOD-like receptor signaling pathway, and T cell receptor signaling pathway were found to be potential signals of HQ-BS in treating cancer. Through PPI network analysis, TNF signaling pathway, tryptophan metabolism, proteoglycans in cancer, cell cycle, and chemical carcinogenesis sub-networks were obtained. Conclusions: HQ-BS contains various bioactive compounds, including flavonoids, phytosterols, and other compounds, and these compounds can inhibit or activate multiple targets and pathways against cancer.

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“…We have showed integration of cdk2 activation into platelet signaling and function ex vivo. There is burgeoning interest and development of pharmacologic mediators directed at cdk2 [85][86][87] . The priority accorded cdk2 as a pharmacologic target is timely given the possible role of cdk2 in the diverse physiology of platelets.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinase 2 (Cdk2) controls phosphatase-regulated signaling and function in platelets

Woods

Hood

Shiva

et al. 2020

Preprint

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Cell cycle regulatory molecules including cyclin-dependent kinases can be recruited into non-nuclear pathways to coordinate cell cycling with the energetic state of the cell or with functions such as motility. Little is known about the role of cell cycle regulators in anucleate cells such as platelets. We report that cyclin-dependent kinase (cdk2) is robustly expressed in human platelets, is activated by thrombin and is required for platelet activation. Cdk2 activation required Src signaling downstream of the platelet thrombin receptor PAR1. Kinase-active cdk2 promoted the activation of downstream platelet kinases by phosphorylating and inactivating the catalytic subunit of protein phosphatase 1 (PP1). Erk was bound to PP1 in a complex with the PP1 regulator PPP1R12a (MYPT1) in platelets, and cdk2 inhibited the phosphatase activity of PP1 and PPP1R12a bound complexes. The requirement for cdk2 in Erk activation could be replaced by the phosphatase inhibitor calyculin if cdk2 was inhibited.Blockade of cdk2 kinase with chemical and peptide cdk2 inhibitors resulted in suppression of thrombin-induced platelet aggregation, and partially inhibited GPIIb/IIIa integrin activation as well as platelet secretion of P-Selectin and ATP. Together, these data indicate a requirement for cdk2 in platelet activation.

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Identification of novel CDK2 inhibitors by a multistage virtual screening method based on SVM, pharmacophore and docking model

Cited by 20 publications

References 33 publications

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

A Network Pharmacology Approach to Explore the Potential Mechanisms of Huangqin-Baishao Herb Pair in Treatment of Cancer

Cyclin-dependent kinase 2 (Cdk2) controls phosphatase-regulated signaling and function in platelets

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