In Silico Identification of Small Molecule Mimetics of the Pro-Apoptotic BH3-Helix

Melanie      Fullbeck; Julia      Hossbach; Ines      S. Jaeger; Peter      T. Daniel; Robert      Preissner

Abstract

Apoptosis, the programmed cell death, is a highly organized process essential for elimination of degenerated cells. Therefore, a tremendous effort is put into the development of new cancer therapeutics, which induce apoptosis in tumor cells. The integration of novel computer-based strategies, which accelerate this development, is a challenging goal. In this context, a variety of terphenyl-based compounds that mimic the alpha-helical region of the pro-apoptotic Bak BH3 domain has already been identified.

These compounds were used as lead compounds for an in silico screening in our database which contains more than four million drug-like molecules. During this screening, the compounds from the virtual database were compared with the lead compounds by 2D and 3D similarities. After additional property filtering and docking experiments, five promising candidates have been validated in vitro experiments to strengthen the in silico results.

Keywords: Apoptosis, Bcl-2, Bak, In silico screening, Molecular docking, BH3-helix, Programmed Cell Death, Degenerated Cell, Membarane Blebbing, DNA Degradation, Fragmentation of Nucleaus, Intrinsic pathway, Extrinic pathway, Death Inducing Lignands, Receptors, Permeabilization