Pharmacophore modeling studies of type I and type II kinase inhibitors of Tie2

Xie, Qingqing; Xie, Hongtu; Ren, Ji-Xia; Li, Linli; Yang, Shengyong

doi:10.1016/j.jmgm.2008.11.008

Cited by 84 publications

(39 citation statements)

References 30 publications

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“…Such a feature is actually found in the fluorescein scaffold and in our pharmacophore model. [84][85][86][87] However pharmacophore models of kinase inhibitors are also characterized by at least one hydrogen bond donor or acceptor not present in our model, therefore supporting the hypothesis of an allosteric binding site. We could also envisage a possible interaction of RB with other proteins that take part in the transport of neurotransmitters and are present in the system such as chloride, potassium channels or kinase such as pyruvate kinase 88 or phosphodiesterase.…”

Section: Vmat2 and Vacht Pharmacologysupporting

confidence: 74%

Rose Bengal analogs and vesicular glutamate transporters (VGLUTs)

Pietrancosta

Kessler

Favre-Besse

et al. 2010

Bioorganic & Medicinal Chemistry

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Section: Vmat2 and Vacht Pharmacologysupporting

confidence: 74%

Rose Bengal analogs and vesicular glutamate transporters (VGLUTs)

Pietrancosta

Kessler

Favre-Besse

et al. 2010

Bioorganic & Medicinal Chemistry

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“…A simpler four-feature model was used to discuss Type II inhibitors by Backes et al [5], resolving ligands into hinge, DFG, Glu-Lys and deep pocket binding components. Quantitative pharmacophore models were developed by Xie et al [14], specifically for Type I and Type II Tie2 protein kinase inhibitors (Tie2 is closely related to VEG-FR-2). Here, a five-feature model was found sufficient to explain Type II Tie2 inhibition, with the additional use of two excluded volume constraints (in the HM region).…”

Section: Discussionmentioning

confidence: 99%

“…Various attempts have been made to qualitatively rationalize the broad structural features that govern Type II protein kinase inhibitor binding [5,[13][14][15]. For example, Backes et al [5] resolved inhibitor features into four groups, which interact with the hinge region, the DFG loop, a Glu-Lys pair and the deep pocket.…”

Section: Introductionmentioning

confidence: 99%

Application of shape-based and pharmacophore-based in silico screens for identification of Type II protein kinase inhibitors

Mucs

Bryce

Bonnet

2011

J Comput Aided Mol Des

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The identification of new, potent and selective inhibitors of important protein kinase targets is a major goal of drug discovery. Here we analyze the crystal structures of 55 protein kinase complexes with Type II inhibitors and find they adopt a conserved twisted V-shape, with an angle of 121 ± 8° and twist of 78 ± 8°. The tightly conserved twist appears important in ensuring ligands curve around the protein backbone and towards the deep pocket. From this, we develop predictive pharmacophore- and shape-based screens to identify Type II inhibitors from a database which also contains Type I inhibitors as decoys. Both approaches exhibit a good level of discrimination for Type II molecules. The most effective pharmacophore model requires six features and three excluded volume regions. Shape-based screening using ROCS generally performs at least as well as pharmacophore approaches. There is only a moderate dependence of shape-based or pharmacophore-based screens on the underlying conformer generator (MOE, Macromodel, Omega and SPE), as well as on ligand linkage chemistry (amide and urea). Finally, we apply our approach to retrieval of Type II inhibitors from a modified version of the DUD database, containing over 104,000 compounds. We observe good enrichment, providing further evidence that the in silico screens developed here will constitute useful guides for identification of small molecule inhibitors targetting protein kinases in their inactive conformational state.

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“…The majority of them contain a hydrogen bond donor-acceptor pair (urea or amide) and a hydrophobic moiety that forms van der Waals interactions with the allosteric site. Moreover, they have a group that forms one or two hydrogen bonds with the kinase hinge region [20].…”

Section: Dfg-motif Dynamicsmentioning

confidence: 99%

Non-ATP Competitive Protein Kinase Inhibitors

Garuti¹,

Roberti²,

Bottegoni

2010

CMC

111

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Protein kinases represent an attractive target in oncology drug discovery. Most of kinase inhibitors are ATP-competitive and are called type I inhibitors. The ATP-binding pocket is highly conserved among members of the kinase family and it is difficult to find selective agents. Moreover, the ATP-competitive inhibitors must compete with high intracellular ATP levels leading to a discrepancy between IC50s measured by biochemical versus cellular assays. The non-ATP competitive inhibitors, called type II and type III inhibitors, offer the possibility to overcome these problems. These inhibitors act by inducing a conformational shift in the target enzyme such that the kinase is no longer able to function. In the DFG-out form, the phenylalanine side chain moves to a new position. This movement creates a hydrophobic pocket available for occupation by the inhibitor. Some common features are present in these inhibitors. They contain a heterocyclic system that forms one or two hydrogen bonds with the kinase hinge residue. They also contain a hydrophobic moiety that occupies the pocket formed by the shift of phenylalanine from the DFG motif. Moreover, all the inhibitors bear a hydrogen bond donor-acceptor pair, usually urea or amide, that links the hinge-binding portion to the hydrophobic moiety and interacts with the allosteric site. Examples of non ATP-competitive inhibitors are available for various kinases. In this review small molecules capable of inducing the DFG-out conformation are reported, especially focusing on structural feature, SAR and biological properties.

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Pharmacophore modeling studies of type I and type II kinase inhibitors of Tie2

Cited by 84 publications

References 30 publications

Rose Bengal analogs and vesicular glutamate transporters (VGLUTs)

Rose Bengal analogs and vesicular glutamate transporters (VGLUTs)

Application of shape-based and pharmacophore-based in silico screens for identification of Type II protein kinase inhibitors

Non-ATP Competitive Protein Kinase Inhibitors

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