Phosphoinositide-3-kinase (PI3K) inhibitors: identification of new scaffolds using virtual screening

Frédérick, Raphaël;Mawson, Claire;Kendall, Jackie D;Chaussade, Claire;Denny, William A;et.al.
(2009) Bioorganic & Medicinal Chemistry Letters : the tetrahedron journal for research at the interface of chemistry and biology — Vol. 19, n° 20, p. 5842-5847 (2009)

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  • Frédérick, Raphaëlorcid-logoUCLouvain
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  • Mawson, Claire
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  • Kendall, Jackie D
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  • Chaussade, Claire
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  • Denny, William A
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Abstract
In the present work, we used virtual screening (VS) of the ZINC database of 2.5 million compounds to seek new PI3K inhibitory scaffolds. The VS flowchart implemented various filters, including a 3D-database screen, and extensive docking studies, to derive 89 derivatives that were experimentally assayed against the four PI3K isoforms. Seven compounds showed inhibitory activities between 1 and 100 microM, with four being sufficiently potent to constitute potential new scaffolds. The binding conformations of these four were analyzed to provide a rationalization of their activity profile.
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Frédérick, R., Mawson, C., Kendall, J. D., Chaussade, C., Rewcastle, G. W., Shepherd, P. R., & Denny, W. A. (2009). Phosphoinositide-3-kinase (PI3K) inhibitors: identification of new scaffolds using virtual screening. Bioorganic & Medicinal Chemistry Letters : the tetrahedron journal for research at the interface of chemistry and biology, 19(20), 5842-5847. https://doi.org/10.1016/j.bmcl.2009.08.087 (Original work published 2009)