General Ser/Thr Kinases Pharmacophore Approach for Selective Kinase Inhibitors Search as Exemplified by Design of Potent and Selective Aurora A Inhibitors |
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Authors: | Natalya I. Vasilevich Elena A. Aksenova Denis N. Kazyulkin Ilya I. Afanasyev |
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Affiliation: | Novie Nauchnie Tekhnologii Ltd. (ASINEX Company Group), Moscow, Russia |
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Abstract: | A general pharmachophore model for various types of Ser/Thr kinases was developed. Search for the molecules fitting to this pharmacophore among ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against several Ser/Thr kinases such as Aurora A, Aurora B and Haspin. The possibility of performing the fine‐tuning of the general Ser/Thr pharmacophore to desired types of kinase to get active and selective inhibitors was exemplified by Aurora A kinase. As a result, several hits in 3–5 nm range of activity against Aurora A kinase with rather good selectivity and ADME properties were obtained. |
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Keywords: | kinase molecular modeling pharmacophore modeling phosphatase structure‐based drug design |
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