Models for Predicting IKKA and IKKB Blockade

Hu, Haipeng; Snyder, James P.

doi:10.1021/ci300287t

Cited by 3 publications

(3 citation statements)

References 45 publications

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“…A number of small molecules have been reported through intensive studies and drug discovery programs for the development of potent and selective IKKβ inhibitors. − In addition to various ATP competitive inhibitors, the allosteric inhibitors have also been shown to selectively impair the activity of IKKβ . Although most IKKβ inhibitors were identified via the high-throughput screening of a chemical library and the structural modifications of known inhibitors, some rational drug design approaches have also been actively pursued based on a variety of computational methods. − However, the lack of 3D structure of IKKβ has limited the applicability of the computational methods due to the considerable uncertainty in estimating the biochemical potencies of putative inhibitors. Recently, X-ray crystal structures of IKKβ have been reported both in the resting form and in complex with a potent inhibitor. , Such structural information about the interactions between IKKβ and small-molecule ligands can greatly aid in the design of more effective IKKβ inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Computational Design and Discovery of Nanomolar Inhibitors of IκB Kinase β

et al. 2015

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IκB kinase β (IKKβ) is a useful target for the discovery of new medicines for cancer and inflammatory diseases. In this study, we aimed to identify new classes of potent IKKβ inhibitors based on structure-based virtual screening, de novo design, and chemical synthesis. To increase the probability of finding actual inhibitors, we improved the scoring function for the estimation of the IKKβ-inhibitor binding affinity by introducing proper solvation free energy and conformational destabilization energy terms for putative inhibitors. Using this modified scoring function, we have been able to identify 15 submicromolar-level IKKβ inhibitors that possess the phenyl-(4-phenyl-pyrimidin-2-yl)-amine moiety as the molecular core. Decomposition analysis of the calculated binding free energies showed that a high biochemical potency could be achieved by lowering the desolvation cost and the conformational destabilization for the inhibitor required for binding to IKKβ as well as by strengthening the interactions in the ATP-binding site. The formation of two hydrogen bonds with backbone amide groups of Cys99 in the hinge region was found to be necessary for tight binding of the inhibitors in the ATP-binding site. From molecular dynamics simulations of IKKβ-inhibitor complexes, we also found that complete dynamic stability of the bidentate hydrogen bond with Cys99 was required for low nanomolar-level inhibitory activity. This implies that the scoring function for virtual screening and de novo design would be further optimized by introducing an additional energy term to measure the dynamic stability of the key interactions in enzyme-inhibitor complexes.

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Section: Introductionmentioning

confidence: 99%

Computational Design and Discovery of Nanomolar Inhibitors of IκB Kinase β

et al. 2015

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“…Other important features of the kinases not captured by Glide docking include the plasticity of the DLG motif and the glycine-rich loop . These aspects are under active investigation for the kinases considered here …”

Section: Resultsmentioning

confidence: 99%

“…44 These aspects are under active investigation for the kinases considered here. 45 The sequence comparisons of Figure 11 likewise address the predominant selectivity for Ser/Thr kinases by the monocarbonyl inhibitors. Of the ≥85% inhibition hits from 4's interrogation of the kinase panel, the sequence identities for the Ser/Thr kinases (Figure 2, orange color) range from 56% to 100% relative to AKT2 while the KDR (Tyr kinase) and NEK1 (dual function kinase) exceptions fall at 33%.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 92%

Monocarbonyl Curcumin Analogues: Heterocyclic Pleiotropic Kinase Inhibitors That Mediate Anticancer Properties

et al. 2013

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Curcumin is a biologically active component of curry powder. A structurally-related class of mimetics possesses similar anti-inflammatory and anticancer properties. Mechanism has been examined by exploring kinase inhibition trends. In a screen of 50 kinases relevant to many forms of cancer, one member of the series (4, EF31) showed ≥85% inhibition for ten of the enzymes at 5 μM, while twenty-two of the proteins were blocked at ≥40%. IC50’s for an expanded set of curcumin analogs established a rank order of potencies, and analyses of IKKβ and AKT2 enzyme kinetics for 4 revealed a mixed inhibition model, ATP competition dominating. Our curcumin mimetics are generally selective for Ser/Thr kinases. Both selectivity and potency trends are compatible with protein sequence comparisons, while modeled kinase binding site geometries deliver a reasonable correlation with mixed inhibition. Overall, these analogs are shown to be pleiotropic inhibitors that operate at multiple points along cell signaling pathways.

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Identification of key genes and pathways associated with topotecan treatment using multiple bioinformatics tools

Kang

Lan²,

Huang³

et al. 2020

Journal of the Chinese Medical Association

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Background: The goal of this study is to determine critical genes and pathways associated with topotecan using publicly accessible bioinformatics tools. Methods: Topotecan signatures were downloaded from the Library of Integrated Network-Based Cellular Signatures (LINCS) database (http://www.ilincs.org/ilincs/). Differentially expressed genes (DEGs) were defined as genes that appeared at least three times with p values <0.05 and a fold change of ≥50% (|log2FC| ≥ 0.58). Hub genes were identified by evaluating the following parameters using a protein-protein interaction network: node degrees, betweenness, and eigenfactor scores. Hub genes and the top-40 DEGs by |log2FC| were used to generate a Venn diagram, and key genes were identified. Functional and pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Information on ovarian cancer patients derived from The Cancer Genome Atlas (TCGA) database was analyzed, and the effect of topotecan on the protein expression was examined by Western blotting. Results: Eleven topotecan signatures were downloaded, and 65 upregulated and 87 downregulated DEGs were identified. Twenty-one hub genes were identified. We identified eight key genes as upregulated genes, including NFKBIA, IKBKB, GADD45A, CDKN1A, and HIST2H2BE, while EZH2, CDC20, and CDK7 were identified as downregulated genes, which play critical roles in the cell cycle and carcinogenesis in KEGG analysis. In the TCGA analysis, the CDKN1A+/EZH2− group had the longest median survival, while the CDKN1A−/EZH2+ group had the shortest median survival. Topotecan-treated murine ovarian (MOSEC), colorectal (CT26), and lung (LLC) cancer cell lines displayed upregulated CDKN1A encoding p21 and downregulated Ezh2. Conclusion: Using publicly accessible bioinformatics tools, we evaluated key genes and pathways related to topotecan and examined the key genes using the TCGA database and in vitro studies.

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Models for Predicting IKKA and IKKB Blockade

Cited by 3 publications

References 45 publications

Computational Design and Discovery of Nanomolar Inhibitors of IκB Kinase β

Computational Design and Discovery of Nanomolar Inhibitors of IκB Kinase β

Monocarbonyl Curcumin Analogues: Heterocyclic Pleiotropic Kinase Inhibitors That Mediate Anticancer Properties

Identification of key genes and pathways associated with topotecan treatment using multiple bioinformatics tools

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