Molecular Docking Study Of HIV-1 IN And Inhibitors

HIV-1 integrase(IN) is an essential enzyme for retroviral replication .It is involved in the integration of HIV DNA into host chromosomal DNA and appears to have no functional equivalent in human cells. Therefore it is an attractive and rational target for selective anti-AIDS therapy. During the past 10 years a plethora of inhibitors have been identified and some were shown to be selective against IN and block viral replication .The two most predominant classes of inhibitors have been the catechol containing hydroxylated aromatics and more recently the diketoacid containing aromatics. And the crystal structure of the HIV-1 IN catalytic domain complexed with an inhibitor 5CITEP as a platform for antiviral drug design has been determined, provides us with the important information about the binding site and the pattern. The purpose of this paper is to discuss the patterns between IN and inhibitors by means of docking method and to probe how the structure-modified of the ligands and receptors affect the interaction between them. To some extent, the work makes reference to design novel inhibitors In the fourth section, the docking study between IN and 5CITEP has been investigated by a docking program called the Affinity. As we know, almost systems of present docking studies only have contained the single Mg ion, so we have compared the difference of the docking study between the inhibitor and the HIV-1 IN catalytic domain containing the single and double Mg ion. Having taken the information of crystal structure into account, we have concluded that the second ion is of importance to the interaction between the ligand and receptor. There exists the obvious difference between the two systems about the energy, the value of the latter is lower than that of the former by about 40kJ/mol. The patterns of interaction between ligand and receptor reduces the two probabilities from the previous four ones. There exist the four patterns in the former system: the first conformation is the key one among the all results. The value of the lowest energy is -55.26 kcal/mol, the tetrazole ring makes the interaction with L63 and is more deeply buried in the active site. And the H atom of the enol group of the ligand interacts with the Q148 by the H-bond. But the observation that in the docking pattern the ligand differ from its X-rays starting position, so we do not adopt the pattern considering the higher total energy of the system and the mechanism of the ligand interacting with the receptor. The second one is quite consistent with the conclusion of the former docking study investigated by the other persons. We choose the conformation whose value of interaction energy is -51.68 kcal/mol as a example to analyse the situation, the tetrazole of the ligand points Q148, and the H atom of the enol group of the ligand interacts with the Q148 as the first pattern and the interaction result in the movement of Q148 by the H-bond, and the value of the distance of O-H is 2.47 ?. The Cl atom of indole ring interacts with N155, which contribute to the defining the indole ring of ligand position in the active site.Because the total energy of the system is very low and the interaction is quite strong, we consider the pattern is reasonable. The third pattern can be classified the two probabilities: a) the Cl atom points the undersurface; b) the Cl atom points the above. The value of the interaction energy is -53.80 kcal/mol, the situation about the ligand is quite resemble with the X-ray position, and the position is more deeply buried in the active site, and the whole structure moves forward the direction of K159. The tetrazole ring does not the interaction with T66, but points the H67 and interacts with each other. There exists the interaction between 443H and the C atom of the indole ring, which is believed to be a major factor in defining the direction of the indole ring. Because of the lower total energy and the similarity to the crystal structure, we conclude that the pattern is reasonable. The value of the interaction energy is -54.24 kcal/mol under the B pattern, the Cl atom rotate into the deeper place of the binding site. The tetrazole ring interacts with K156,D64 respectively, and the O atom of the enol group makes interaction with I151.So the whole position of the tetrazole ring is located between K156 and K159 and is intensified in the site. The pattern can provide the further MD study with the relative information of ligand and be consistent with the conclusion of the former docking study, the conformation is believed to be reasonable. The fourth pattern can be deleted considering the great difference in the interaction energy of the former pattern and the conclusion which is proved reasonable. There exist the two patterns in latter system, the interaction energy is lower than the former one. The second Mg2+ plays a key role in the interaction between...