Virtual Screening of Small Drug-Like Compounds Stimulating the Enzymatic Activity of Kallikrein-Related Peptidase 3 (KLK3)

• Published in: ChemMedChem 2016-09, Vol.11 (18), p.2043-2049
• Main Authors: Ylikangas, Henna, Mattsson, Johanna M., Stenman, Ulf-Håkan, Koistinen, Hannu, Poso, Antti, Lahtela-Kakkonen, Maija
• Format: Article
• Language: English
• Subjects: angiogenesis; cancer; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Activation - drug effects; Humans; kallikrein; Kallikreins - metabolism; molecular modeling; Molecular Structure; Prostate-Specific Antigen - metabolism; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; virtual screening
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201600181

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. A firm nudge for KLK3: New drug‐like small molecules were discovered that stimulate the enzymatic activity of kallikrein‐related peptidase 3 (KLK3). The most potent one stimulates KLK3 activity in synergy with cyclic peptides by approximately 350 % and shows a dose‐dependent effect. This is evidence that such molecules are beneficial tools for studying the enzymatic activity and antiangiogenic properties of KLK3.