Development of new inhibitors for kelch-like ECH related protein 1 and nuclear factor erythroid 2 related factor 2 protein interaction with molecular modeling applications

NRF2 (Nuclear Factor Erythroid 2 Related Factor 2) is a key transcription factor in the regulation of the cellular antioxidant response in humans. Additionally, NRF2 is an important leucine zipper (bZIP) protein that regulates the expression of antioxidant protein that protects against oxidative stress resulting from inflammation or damage. Under conditions of oxidative stress or inflammation, the activity of KEAP1 decreases and NRF2 accumulates in the nucleus. In this way, KEAP1 functions as a critical sensor of cellular stress. The KEAP1- NRF2-ARE pathway is the main protection mechanism that neutralizes oxidative stress. This pathway has a protective effect on many diseases such as cancer, cardiovascular diseases, diabetes, and autoimmune diseases. In recent years, pharmacological inhibition of this pathway has become promising for the treatment of many chronic diseases characterized by oxidative stress. This study aims to develop new inhibitors targeting the KEAP1-NRF2 interaction using molecular modeling techniques. In this direction, 400 chemical compounds scanned from the ChEMBL and BindingDB databases will be examined by the molecular docking method. In addition, the basic parameters affecting drug metabolism such as Absorption, Distribution, Metabolism, and Elimination (ADME) properties of these compounds in the body and their pharmacokinetic compatibility will be evaluated. Thus, it is aimed to develop new, more effective agents with low side effects targeting the KEAP1-NRF2 pathway, which acts as a regulator of oxidative stress involved in various pathophysiological processes, including cancer, cardiovascular diseases, diabetes, and neurodegenerative disorders, by using molecular modeling methods. As a result, the development of new inhibitors for this pathway targets to present a thesis study with high added value in scientific and economic terms by minimizing time, cost and manpower requirements.