title: Virtual Screening of Small Drug-Like Compounds Stimulating the Enzymatic Activity of Kallikrein-Related Peptidase 3 (KLK3).
abstract: Kallikrein-related peptidase 3 (KLK3) is a prostatic serine protease shown to possess antiangiogenic properties which are exerted via its proteolytic activity. The antiangiogenic effect indicates that KLK3 may slow down the growth of prostate cancer; this makes it an interesting target for new therapies for prostate cancer. In this work, new drug-like compounds were discovered that stimulate the proteolytic activity of KLK3. The compounds were identified using 2D similarity search and 3D pharmacophore-based virtual screening, and their ability to stimulate KLK3 was verified by enzymatic activity assays. The effect of the molecules alone was modest, but in synergy with a cyclic peptide the most potent molecule was found to stimulate KLK3 activity significantly: up to 351 % of the activity of KLK3. This demonstrates that small drug-like compounds can be beneficial tools in studying the antiangiogenic properties of KLK3.
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. Henna.Ylikangas@uef.fi.
authors.forename: Henna
authors.initials: H
authors.lastname: Ylikangas
authors.affiliation: Department of Clinical Chemistry, Biomedicum Helsinki, University ofHelsinki and, Helsinki University Central Hospital, 00014, Helsinki, Finland.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Mattsson
authors.affiliation: Department of Clinical Chemistry, Biomedicum Helsinki, University ofHelsinki and, Helsinki University Central Hospital, 00014, Helsinki, Finland.
authors.forename: Ulf-Håkan
authors.initials: UH
authors.lastname: Stenman
authors.affiliation: Department of Clinical Chemistry, Biomedicum Helsinki, University ofHelsinki and, Helsinki University Central Hospital, 00014, Helsinki, Finland.
authors.forename: Hannu
authors.initials: H
authors.lastname: Koistinen
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.|University Hospital Tübingen, Department of Internal Medicine 1, Division of Molecular Oncology of Solid Tumors, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Lahtela-Kakkonen
mesh_terms: D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007610:Kallikreins / Q000378:metabolism*; D015394:Molecular Structure; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D054852:Small Molecule Libraries; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: angiogenesis; cancer; kallikrein; molecular modeling; virtual screening