| Gene drugs have become one of the hot research topics because they give us a wonderful hope to overcome all diseases. Aromatic diamidines (dicationic molecules), which have been recognized as the powerful gene drug candidates over the past decades, can bind in the DNA minor groove, inhibit the duplication of morbid sequences, and fight against a number of human and animal diseases. In practical application, however, the high selective binding to DNA is more important when they are used as anticancer drugs or specific gene modifiers. Even though some valuable experimental results on the interaction of diamidines with DNA, however, investigations on how diamidines interact with DNA are quite limited until now. It is a difficult subject to understand essentially these important information mentioned above, unless we can obtain more details at the molecular level. In this thesis, binding modes and interactions of aromatic diamidines with DNA were carried out using theoretical methods, such as, molecular docking and molecular dynamics simulation. The main obtained results in this work list as follows: In the first section, on the basis of the binding models of aromatic diamidines with DNA, the important influencing factors for the binding affinity of aromatic diamidines with DNA were systematically analyzed; In the second section, molecular dynamics simulations have been adopted to investigate the details of the interaction between aromatic diamidines and DNA.The first issue is entitled "docking study on key influencing factors of binding affinity for aromatic diamidine drugs with DNA ". Docking simulations of aromatic diamidines DB75, DB293, DB921, DB884, and their analogues to the B-DNA minor groove has provided insight into the different factors affecting the DNA binding affinity of aromatic diamidines.40aromatic diamidines are involved in this paper. According to the docking results, it can be found that the curvature, length, distal group and heteroaromatic rings are four important factors that would influence the DNA binding affinity of aromatic diamidines. Firstly, the better the curvature of the aromatic diamidine fits DNA minor groove, the higher the binding affinity is. Secondly, increasing the molecular length within certain range can make the binding affinity higher. But the overlong molecular length has no benefit for the binding affinity of aromatic diamidines. Thirdly, changing the distal group of aromatic diamidines from amidino to imidazole or pyrimidine is favorable for improving the binding affinity of aromatic diamidines. Fourthly, the introduction of heteroaromatic rings of aromatic diamidines influences their binding affinities. Finally, these favorable factors are considered in one molecule DB103d which has a significantly larger binding affinity than the other aromatic diamidines studied in this work.The second topic is “Binding properties and conformational dynamics of aromatic diamidines that have different distal groups with DNA from a theoretical view." We present here molecular dynamics simulations for DB1883-DNA, DB1803-DNA, and DB1804-DNA adducts. In the simulation process, aromatic diamidines bound stably in AATT regions of B-DNA minor groove. The carbon atoms in imidazole or pyrimidine of DB1803and DB1804can form hydrogen bonds with DNA base pairs. DB1803and DB1804can form more hydrogen bonds with DNA than that of DB1883. Moreover, between the carbon atoms in imidazole or pyrimidine and DNA base pairs, there are also water-mediated hydrogen-bonding interactions. This explains well that DB1803and DB1804have stronger binding affinity with DNA than DB1883. Binding free energies calculated using MM_PBSA methods reveal that the binding interaction of the three aromatic diamidines with DNA is enthalpy driven, associated with an entropic penalty. All of these findings not only provide useful information to help people better understand the binding properties of the aromatic diamidines, but also provide new ideas for design of new drug candidates. |
PDF Full Text Request