title: A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods.
abstract: Allosteric modifiers have the potential to fine-tune enzyme activity. Therefore, targeting allosteric sites is gaining increasing recognition as a strategy in drug design. Here we report the use of computational methods for the discovery of the first small-molecule allosteric inhibitor of the collagenolytic cysteine peptidase cathepsin K, a major target for the treatment of osteoporosis. The molecule NSC13345 is identified by high-throughput docking of compound libraries to surface sites on the peptidase that are connected to the active site by an evolutionarily conserved network of residues (protein sector). The crystal structure of the complex shows that NSC13345 binds to a novel allosteric site on cathepsin K. The compound acts as a hyperbolic mixed modifier in the presence of a synthetic substrate, it completely inhibits collagen degradation and has good selectivity for cathepsin K over related enzymes. Altogether, these properties qualify our methodology and NSC13345 as promising candidates for allosteric drug design.
authors: 1] Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland [2] Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Cesta v Mestni log 88A, SI-1000 Ljubljana, Slovenia.
authors: Marko
authors: M
authors: Novinec
authors: Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Cesta v Mestni log 88A, SI-1000 Ljubljana, Slovenia.
authors: Matevž
authors: M
authors: Korenč
authors: Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors: Amedeo
authors: A
authors: Caflisch
authors: Green Center for Systems Biology, UT Southwestern Medical Center, 6001 Forest Park Blvd., Dallas, Texas 75390-9050, USA.
authors: Rama
authors: R
authors: Ranganathan
authors: 1] Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Cesta v Mestni log 88A, SI-1000 Ljubljana, Slovenia [2] Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Jamova cesta 39, SI-1000 Ljubljana, Slovenia.
authors: Brigita
authors: B
authors: Lenarčič
authors: Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors: Antonio
authors: A
authors: Baici
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D001565:Benzoates / Q000378:metabolism; D056657:Cathepsin K / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D010024:Osteoporosis / Q000188:drug therapy / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D001565:Benzoates; C000601669:NSC13345; D056657:Cathepsin K