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Issue 5, 2020
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Computer-aided discovery of phenylpyrazole based amides as potent S6K1 inhibitors

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Abstract

Ribosomal protein S6 kinase beta-1 (S6K1) is an attractive therapeutic target. In this study, computational analysis of five thiophene urea-based S6K1 inhibitors was performed. Molecular docking showed that the five compounds formed hydrogen bonds with residues Glu173 and Leu175 of S6K1 and hydrophobic interactions with residues Val105, Leu97 and Met225, and these interactions were key elements for the inhibitory potency of the compounds. Binding free energy (ΔGbind) decomposition analysis showed that Leu97, Glu173, Val 105, Leu175, Leu97 and Met225 contribute the most to ΔGbind. Based on the computer results, phenylpyrazole based amides (D1–D3) were designed and synthesized. Biological evaluation revealed that D2 exhibited 15.9 nM S6K1 inhibition, medium microsomal stability and desirable bioavailability.

Graphical abstract: Computer-aided discovery of phenylpyrazole based amides as potent S6K1 inhibitors

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Supplementary files

Article information


Submitted
15 Nov 2019
Accepted
04 Apr 2020
First published
30 Apr 2020

RSC Med. Chem., 2020,11, 583-590
Article type
Research Article

Computer-aided discovery of phenylpyrazole based amides as potent S6K1 inhibitors

Y. Yin, Y. Sun, L. Zhao, J. Pan and Y. Feng, RSC Med. Chem., 2020, 11, 583
DOI: 10.1039/C9MD00537D

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