Mechanism of Deoxyguanosine Kinase Inhibition by Nucleotide Derivatives: A Molecular Dynamic Approach

摘要

Deoxyguanosine kinase is the enzyme catalyzing the first rate limiting step in the salvage pathway of purine nucleotide biosynthesis. Deoxy guanosine 5? triphosphate, (dGTP) is the axial product of the enzyme reaction. dGTP at increased concentration acts as strong inhibitor of the enzyme. dGTP also inhibits the de novo biosynthesis of purine nucleotides and consequently diminishes the cellular reservoirs of purine nucleotides. Nucleotide insufficiency induced by dGTP prevents DNA synthesis and cellular proliferation. In this way dGTP could be considered for treatment of viral infectious or even cancerous disorders. Molecular Dynamic (MD) study of deoxyguanosine kinase interaction with its inhibitors helps to survey of the structural determinant elements to design more effective inhibitors. In the present work the well known inhibitors of deoxyguanosine kinase including: deoxyguanosine (mono di and triphosphate) and deoxyinosine (mono and tri phosphate) nucleotides for a molecular dynamic simulation was used. Enzyme-Inhibitor complex were obtained using HEX docking software. The best resulting complexes from docking experiments were used for MD simulations. Enzyme-inhibitors complexes were simulated in aqueous solutions at 37°C and 1 atmosphere of pressure. The out put trajectories were used to extract the simulation data. Present results show that nucleotide inhibitors based on their binding pattern could be divided into two classes, deoxyguanosine mono and di phosphates, bind in the proximity of enzyme active site acting as competitive inhibitors and deoxyinosine mono and triphosphate and guanosine triphosphate bind in sites far from the enzyme active site and acting as non competitive inhibitors. Considering present findings it can conclude first, that dGTP the more potent inhibitor is attached to a non-competitive binding site at the C-terminus of enzyme. dGTP is interacting with the negative and positive groups on its binding site, pulling the positive and pushing negative groups of that site deforming the enzyme structure and inhibits the enzyme more effectively. Second, the more negative charges on dGTP in contrast to other inhibitors seems to promote the inhibition more pronounced.