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ID: ALA2046411

Journal: ACS Med Chem Lett

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

Authors: Liang G, Chen X, Aldous S, Pu SF, Mehdi S, Powers E, Giovanni A, Kongsamut S, Xia T, Zhang Y, Wang R, Gao Z, Merriman G, McLean LR, Morize I.

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.

CiteXplore: 24900446

DOI: 10.1021/ml200291e