Bioinformatics and conventional approaches to discover novel biotherapeutics for the treatment of chronic diseases

Abstract

Chronic diseases are a cause of premature mortality and disability in most developing and developed countries, and due to the combination of genetic, physiological, environmental, and behavior factors. Among various chronic diseases, the prevalence of diabetes and cancer is increasing exponentially every year in Mexico and in other countries. In diabetes and cancer, glucose metabolism plays a vital role, and it is proven that inhibition of serine-protease dipeptidyl peptidase-4 (DPP4) regulates glucose metabolism and provides a therapeutic opportunity. Current therapeutics in clinical use for both diabetes and cancer possess side effects, and hence, there is a need for the development of new therapeutics. Nature is a source of diverse bioactive compounds and an important source of potential leads that has been utilized in the process of drug discovery and drug development for many years. Hence, this study was focused on the identification of bioactive compounds for inhibition of DPP4, which possesses the ability to regulate glucose metabolism in skeletal muscle cells, and benefits the treatment of diabetic myopathy in combination with insulin. The first part of this thesis led to the identification of natural compounds chrysin and galangin as DPP4 inhibitors. It was observed that selected natural compounds in combination with insulin improved skeletal muscle health, that benefits the treatment of diabetes and in specific to diabetes myopathy. Network biology approach led to identify significant pathways responsible for the benefits of skeletal muscle health. Since DPP4 inhibition induce Lysine specific demethylase-1 (LSD1) inhibition and thereby possesses anticancer activity. As chrysin and galangin were already proved to possess anticancer activity, bioinformatics approaches led to discover new polyphenol 3- hydroxyflavone as DPP4 inhibitor and LSD1 inhibitor. The polyphenol 3-hydroxyflavone possessed anticancer activity and had found to be highly effective on lung adenocarcinoma cells whose IC50 is almost equal to the therapeutic drugs in clinical use. Another part of this study involved in the isolation of therapeutic proteins from Allium sativum (Garlic or Ajo) as a natural source of bioactive compounds, which possesed DPP4 and LSD1 inhibition activity. It was observed that calmodulin modulating proteins from Allium sativum possessed LSD1 inhibition, and had proven to reduce lung cancer cell proliferation.