Fragment‐Based Drug Discovery of Kinase Inhibitors

Erlanson, Daniel A.

doi:10.1002/9780470524961.ch18

Cited by 3 publications

(3 citation statements)

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“…68,78 ■ CONCLUSIONS FBDD strategies have proven very successful in the development of PDE inhibitors across the PDE gene superfamily, much akin to results seen for other gene families such as the protein kinases. 47,79,80 FBDD techniques can also be used to produce chemical probes targeting the PDEs, as well as lead compounds, and candidate drugs. The programs targeting PDEs described here demonstrate how initial fragment hits can be developed into promising and highly selective lead compounds.…”

Section: ■ Fragment-sized Pde Inhibitorsmentioning

confidence: 99%

Fragment-Based Drug Discovery of Phosphodiesterase Inhibitors

Svensson

Bender

Bailey³

2017

J. Med. Chem.

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Phosphodiesterases are proving to be fruitful targets for drug discovery. At the same time fragment-based drug discovery has matured into a powerful and widely applied technique. In this communication we review the application of fragment-based drug discovery for the successful identification of novel 3',5'-cyclic nucleotide phosphodiesterase (PDE) inhibitors, concentrating on both experimental and computational strategies for fragment screening and hit-to-lead development. To this end, we also mine the open access databases ChEMBL and PDB for fragments showing PDE inhibitory activity, as well as SureChEMBL for recent PDE related patents, to provide a wider context for exploring fragment diversity. Together these approaches form an integrated experimental and computational platform to exploit fragment-based drug discovery for this important gene superfamily.

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Section: ■ Fragment-sized Pde Inhibitorsmentioning

confidence: 99%

Fragment-Based Drug Discovery of Phosphodiesterase Inhibitors

Svensson

Bender

Bailey³

2017

J. Med. Chem.

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“…MAPK signaling pathways are well-conserved and include members of four subfamilies: extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), Nemo-like kinase (NLK), and p38 MAP kinase (6). In many organisms, the p38 subfamily has four isoforms identified (p38 α/β/γ/δ) that interact with a diverse number of regulatory mechanisms (7–9), many of which are related to stress responses, inflammation, and apoptosis (10, 11).…”

Section: Introductionmentioning

confidence: 99%

Smp38 MAP Kinase Regulation in Schistosoma mansoni: Roles in Survival, Oviposition, and Protection Against Oxidative Stress

et al. 2019

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Eukaryotic protein kinases (ePKs) are good medical targets for drug development in different biological systems. ePKs participate in many cellular processes, including the p38 MAPK regulation of homeostasis upon oxidative stress. We propose to assess the role of Smp38 MAPK signaling pathway in Schistosoma mansoni development and protection against oxidative stress, parasite survival, and also to elucidate which target genes have their expression regulated by Smp38 MAPK. After a significant reduction of up to 84% in the transcription level by Smp38 MAPK gene knockdown, no visible phenotypic changes were reported in schistosomula in culture. The development of adult worms was tested in vivo in mice infected with the Smp38 knocked-down schistosomula. It was observed that Smp38 MAPK has an essential role in the transformation and survival of the parasites as a low number of adult worms was recovered. Smp38 knockdown also resulted in decreased egg production, damaged adult worm tegument, and underdeveloped ovaries in females. Furthermore, only ~13% of the eggs produced developed into mature eggs. Our results suggest that inhibition of the Smp38 MAPK activity interfere in parasites protection against reactive oxygen species. Smp38 knockdown in adult worms resulted in 80% reduction in transcription levels on the 10th day, with consequent reduction of 94.4% in oviposition in vitro. In order to search for Smp38 MAPK pathway regulated genes, we used an RNASeq approach and identified 1,154 DEGs in Smp38 knockdown schistosomula. A substantial proportion of DEGs encode proteins with unknown function. The results indicate that Smp38 regulates essential signaling pathways for the establishment of parasite homeostasis, including genes related to antioxidant defense, structural composition of ribosomes, spliceosomes, cytoskeleton, as well as, purine and pyrimidine metabolism pathways. Our data show that the Smp38 MAPK signaling pathway is a critical route for parasite development and may present attractive therapeutic targets for the treatment and control of schistosomiasis.

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“…Drug design using modern procedures, such as the fragment-based approach, do not guarantee that off-target activities are absent: sorafenib, a multikinase inhibitor discovered following this strategy [15], was recently shown to be a nanomolar antagonist of the 5-HT receptors [16]. This issue probably will be successfully reduced in the future by means of in silico procedures, since computational chemistry is developing strategies to predict the promiscuous binding propensities of drug molecules [16].…”

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confidence: 99%