Modeling, Simulation, Docking Studies of Tyrosine Kinase Involved in Leukemia and Microwave Synthesis of Quinazoline Derivatives

Abstract

Acute Mylenoid Leukemia is a type of cancer which affects blood and bone marrow and is characterized by an abnormal proliferation of white blood cells. A number of genes are involved in regulating heamatopoiesis, and thereby affecting the susceptibility to Leukemia.One among them Tyrosine kinase which plays an important role in cell proliferation and differentiation. In this work three dimensional model of Tyrosine kinase was generated using 1Z3S as a template with the help of Modeller7v7. With the aid of the molecular mechanics and molecular dynamics methods, the final model is obtained and is further assessed by Procheck and Verify 3D graph programs, which showed that the final refined model is reliable. After energy minimization the three dimensional structure of Tyrosine was compared with template. Molecular docking of 6-thiogunaosine (6-TG) analogs was performed on the ATR1 model and selective inhibitor was selected based on the docking results. The docking results showed that the three residues in the Tyrosine kinase (GSN235, AsN257, and ILE289) were essential for making hydrogen bond with the analogues. The data presented here strongly indicate that the interactions of these four residues are necessary for a stronger binding of the Tyrosine kinase with synthesized molecules. Also, the study proposed analogues were an effecctive inhibitors by the comparison of docking energy.(1h)-Dione derivatives were not possible because of stearic hindrance by bulky groups present on the nitrogen atoms.