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Virtual Screening and X-ray Crystallography for Human Kallikrein 6 Inhibitors with an Amidinothiophene P1 Group.

ABSTRACT: A series of compounds with an amidinothiophene P1 group and a pyrrolidinone-sulphonamide scaffold linker was identified as potent inhibitors of human kallikrein 6 by structure-based virtual screening based on the union accessible binding space of serine proteases. As the first series of potent nonmechanism-based hK6 inhibitors, they may be used as tool compounds for target validation. An X-ray structure of a representative compound complexed with hK6, resolved at a resolution of 1.88 Å, revealed that the amidinothiophene moiety bound in the S1 pocket and the pyrrolidinone-sulphonamide linker projected the aromatic tail into the S' pocket.

SUBMITTER: Liang G

PROVIDER: S-EPMC4025863 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Virtual Screening and X-ray Crystallography for Human Kallikrein 6 Inhibitors with an Amidinothiophene P1 Group.

Liang Guyan G Chen Xin X Aldous Suzanne S Pu Su-Fen SF Mehdi Shujaath S Powers Elaine E Giovanni Andrew A Kongsamut Sathapana S Xia Tianhui T Zhang Ying Y Wang Rachel R Gao Zhongli Z Merriman Gregory G McLean Larry R LR Morize Isabelle I

ACS medicinal chemistry letters 20120111 2

A series of compounds with an amidinothiophene P1 group and a pyrrolidinone-sulphonamide scaffold linker was identified as potent inhibitors of human kallikrein 6 by structure-based virtual screening based on the union accessible binding space of serine proteases. As the first series of potent nonmechanism-based hK6 inhibitors, they may be used as tool compounds for target validation. An X-ray structure of a representative compound complexed with hK6, resolved at a resolution of 1.88 Å, revealed ...[more]

PMID: 24900446

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