Development of new inhibitors for the treatment of chronic myeloid leukemia by computer aided drug design methods

The Bcr/Abl1 fusion protein which responsible for the pathogenesis of chronic myeloid leukemia (CML) is the main pathogenic factor of the disease with its continuously active tyrosine kinase activity. Standard treatment is Abl1 kinase inhibition with tyrosine kinase inhibitors (TKIs). However, the side effects and drug resistance of these drugs are the handicaps of the treatment. Accordingly, in this thesis study, it was aimed to develop new drug candidate molecules that are more effective and have less side effects than the existing drug molecules for the treatment of CML. In the first stage, three-dimensional structure analyzes of the target proteins and structure optimizations of the compounds obtained from ZINC (version 20th) were performed. In the second step, the ADMET (absorption, distribution, metabolism, excretion, toxicity) properties of the compounds were evaluated in terms of pharmacokinetics. In the third stage, the interaction mechanism between the selected enzymes and chemical compounds for the Type I and Type II inhibition mechanism in the target wildtype and mutant forms was investigated by molecular docking method. According to the molecular docking analysis for the type I inhibition mechanism, the compounds with highest binding affinity were compound 911 to the wildtype enzyme with a binding energy of -14.91 kcal/mol and compound 972 to the mutant enzyme with a binding energy of -14.27 kcal/mol. According to the molecular docking analysis for the Type II inhibition mechanism, the compounds with highest binding affinity were compound 261 in wildtype enzyme with -17.05 kcal/mol binding energy and compound 966 to the mutant enzyme with binding energy of -16.29 kcal/mol. In addition, compound 972 which has the best Type I binding affinity for the mutant Abl1 kinase enzyme is the most suitable drug candidate molecule among other compounds due to its very low solubility, non-toxicity and moderate absorption in ADMET analysis. It is recommended that this study should be evaluated with advanced computational molecular simulation and in vitro studies.