title: 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.
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Guyan
authors.initials: G
authors.lastname: Liang
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Aldous
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Su-Fen
authors.initials: SF
authors.lastname: Pu
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Shujaath
authors.initials: S
authors.lastname: Mehdi
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Elaine
authors.initials: E
authors.lastname: Powers
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Giovanni
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Sathapana
authors.initials: S
authors.lastname: Kongsamut
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Tianhui
authors.initials: T
authors.lastname: Xia
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Wang
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Gregory
authors.initials: G
authors.lastname: Merriman
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Larry R
authors.initials: LR
authors.lastname: McLean
authors.affiliation: Molecular Innovative Therapeutics, Fibrosis and Wound Repair, Global Pharmacovigilance & Epidemiology, Immunology and Inflammation Unit, Early to Candidate Unit, Aging Therapeutic Unit, and Biologics, Sanofi Pharmaceuticals , 1041 Route 202/206, Mailstop 203A, Bridgewater, New Jersey 08807, United States.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Morize
keywords: X-ray crystallography; human kallikrein 6; inhibitor; molecular modeling; multiple sclerosis; serine protease; virtual screening