Theoretical Study On The Stabilities Of Conformations And N-glycosidic Bond Of 2',3'-Dideoxy-2',3'-Didehydroguanosine(D4G)

Nucleoside antiviral drugs are very important to treat AIDS, herpes, hepatitis and other viral diseases. 2', 3'- dehydro-2', 3'- deoxyguanosine (D4G) is a potential anti-HIV and hepatitis virus drugs. The research on D4G molecular structure and property in gas phase and the solution environment is the basis to learn D4G how to bring into play its effect. The theory study on D4G molecular structure and properties in gas phase and the solution environment in this paper.The DFT (B3LYP/6-31+G**) method was used to study the conformational stabilities and isomerization of the isolated and monohydrated 2',3'-dideoxy-2',3'-didehydroguanosine (D4G) molecules in gas phase. The effects of one-water molecule on relative stabilities, conformational parameters and nature charges of D4G were analyzed. The results indicate that there are 8 stable conformers for D4G in gas phase. The conformer d4g-2 is the most stable form of all conformations in gas phase. The relative stability order is as follows: d4g-2> d4g-1> d4g-5> d4g-3> d4g-6> d4g-4> d4g-8> d4g-7. The computational results are in good agreement with the available experimental ones. Addition of one-water molecule did not almost change the order of the relative stability and increased slightly the energy barriers of conformational isomerization of D4G. Hydrogen bonding performed an important role in D4G conformations.One water molecule has little impact on the conformation-angle and the dihedral angle. The existence of water molecules are made of the atomic negative charge become more negative, and positive charge more positive, and also the D4G conformational change each other become more difficult than that in the gas phase. The compound relative stability order of is as follows: d4g-2-h2o> d4g-1-h2o> d4g-5-h2o> d4g-3-h2o> d4g-6-h2o> d4g-8-h2o> d4g-4-h2o> d4g-7-h2o.The calculating on the N-glycosidic bond in the modified nucleoside compounds by protonation contribute to the understanding of the changes of N-glycosidic bond Stability , Which will help us to better understand acid-catalyzed hydrolysis mechanism of modified nucleoside compounds. In the third chapter, we research the N-glycosidic bond stability of D4G in the acid environment. There are three main electronegative centers in the alkali base of D4G as N (3), N (7) and O (11) atom, where are protonized. We were considered a negative One proton and two attract the three center are considered separately. The results show that in the lower acidity of a single proton, the order of N-glycosidic bond stability is as O11H >N3H> N7H. the change are more markedness at bond, charge of the conformation when two protons attract D4G than one proton.D4G protonation are more easy in higher acidity,and N-glycosidic bond stability become greatly weaken, thus forming sugar degradation and guanine. N (3) - (7) center will be of great advantage when three pairs of electronegative center under the protonation competition.