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  Computational Docking Studies of Novel Heterocyclic Carboxamides as Potential PI3Kα Inhibitors

Sweidan, K., Sabbah, D., Engelmann, J., Abdel-Halim, H., & Abu Sheikha, G. (2015). Computational Docking Studies of Novel Heterocyclic Carboxamides as Potential PI3Kα Inhibitors. Letters in Drug Design Discovery, 12(10), 856-863. doi:10.2174/1570180812666150529205248.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-437C-F Version Permalink: http://hdl.handle.net/21.11116/0000-0000-B483-0
Genre: Journal Article

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 Creators:
Sweidan, K1, Author              
Sabbah, DA, Author
Engelmann, J1, Author              
Abdel-Halim, H, Author
Abu Sheikha, G, Author
Affiliations:
1Department High-Field Magnetic Resonance, Max Planck Institute for Biological Cybernetics, Max Planck Society, ou_1497796              

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 Abstract: Drugs comprising a heterocyclic system show widespread therapeutic impact such as antimicrobial, antidepressant, antihypertensive, and anticancer activity. We describe herein computational studies that support the promising biological activity of four new compounds (5, 6, 10 and 13). The wild-type and mutant phosphatidylinositol-4,5-bisphosphate 3-kinaseα (PI3Kα) proteins were used as models to explore the potential interaction of the designed molecules with this important kinase involved in the growth regulation of cancer cells. The results of our studies showed that the verified compounds ought to fit into the kinase domain of wild-type and mutant PI3Kαs. It is predicted that they interact with S774, K802, Y836, V851, S854, T856, Q859, and D933 that are known to be key binding residues for active inhibitors both in wild-type and mutant PI3Kαs. Docking scores infer the selectivity of compounds 5, 6 and 10 toward the mutant PI3Kα (H1047R), whereas compound 13 displayed a slightly higher affinity to the wild-type protein. The pharmacophore modeling of PI3Kα inhibitors showed that the explored compounds shared four out of five pharmacophoric points with such inhibitors. Thus, the recently developed four compounds might be recruited as lead structures for the design of new antitumor drugs targeting PI3Kα.

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 Dates: 2015-12
 Publication Status: Published in print
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 Rev. Type: -
 Identifiers: DOI: 10.2174/1570180812666150529205248
BibTex Citekey: SweidanSEAA2015
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Title: Letters in Drug Design Discovery
Source Genre: Journal
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Pages: - Volume / Issue: 12 (10) Sequence Number: - Start / End Page: 856 - 863 Identifier: -