Computer design og inhibitors of proteinkinase MST1 - the key regulator of apoptosis of β-cells

Abstract

At present time, diabetes is regarded as polygenic, multifactorial disease: genetic predisposition in combination with environmental triggers activates specific autoimmune processes, which lead to the death of β-cells. Therefore, violations in the processes of initiation and implementation of apoptosis are fundamental in the development of the disease. Preservation or restoration of pancreatic β-cells in diabetic patients is an ultimate therapy for diabetes, but is an unmet medical challenge Protein kinase MST1 has been recently identified as a key mediator of cell apoptosis, and recent studies have shown that it could serve as a target for developing new drugs to treat diabetes. In order to find active compounds capable to inhibit MST1 (Mammalian sterile 20-like kinase 1), we carried out a computer-aided design, using methods based on the structure of macromolecule-target (Target-Based Drug Design) and methods based on the structure of ligands (Ligand-Based Drug Design). To assess the undesirable effects we used the computer program PASS (Prediction of Activity Spectra for Substances); for construction of quantitative relationships «structure-activity» (Quantitative Structure-Activity Relationship) and evaluation of inhibitory activity computer program GUSAR (General Unrestricted Structure-Activity Relationships) was used. As a result of experiment, 6 potential inhibitors of MST1were selected. These compounds do not exhibit mutagenic or toxic properties but have high level of activity in comparison with already known inhibitors. This fact makes it possible to suppose, that our compounds are suitable for future synthesis and in vitro screening.