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.

Keywords: angiogenesis; cancer; kallikrein; molecular modeling; virtual screening.