Human kallikrein 6 inhibitors with a para-amidobenzylanmine P1 group identified through virtual screening

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Abstract

A series of hK6 inhibitors with a para-amidobenzylamine P1 group and a 2-hydroxybenzamide scaffold linker was discovered through virtual screening. The X-ray structure of hK6 complexed with compound 9b was determined to a resolution of 1.68 Å. The tertiary folding of the hK6 complexed with the inhibitor is conserved relative to the structure of the apo-protein, whereas the interaction between hK6 and the inhibitor is consistent with both the SAR and the in silico model used in the virtual screening.

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Acknowledgments

Authors would like to thank Drs. Sukanthini Thurairatnam, Larry McLean, Isabelle Morize, and David Lythgoe for support and to thank Drs. Sheng-Yuh Tang, Dirk Friedrich, and Henning Steinhagen for helpful discussions.

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