Molecular Simulation Studies In Discovery Of HIV-1 And H5N1 Inhibitors

AIDS and avian influenza are two serious diseases threatening human life and health. Nowdays,there are some anti-HIV-1 or anti-influenza drugs. However, because of the drug toxicity and viral resistance, researching and development of new, efficient antiviral drugs has important practical significance.Theoretically, the propagation can be controlled if any process of viral life cycle is blocked. Therefore, researches mainly focus on the key proteins of viral replication process. HIV-1 Tat plays a crucial role in transcription and replication of the viral RNA. It promotes productive elongation of HIV mRNA by specific binding with P-TEFb. Thus, Tat-P-TEFb complex is considered as an important potential drug target site. But its detailed mechanism is currently not very clear. Therefore, to explore the mechanism of interaction between HIV-1 Tat and P-TEFb, and find the active site for antiviral could be used as basis for drug design.HIV-1 trans-activating transcription is closely related with the phosphorylation induced by Tat protein. Flavopiridol competitively prevents ATP binding with CDK9, blocks the phosphorylation, to inhibit HIV-1 replication. Therefore, to explore the interaction of molecular information from the perspective of inhibitors, can be useful in understanding of the active site and HIV-1 inhibitors design. Highly pathogenic H5N1 avian influenza virus has been a serious threat to human life and health, the possibility of a global flu pandemic caused by H5N1 has caused worldwide concern. Mechanism of the virus and the antiviral drugs become a research hotspot. Among the key proteins of H5N1, RNA polymerase is relatively stable. The binding site of H5N1 RNA polymerase subunit PA interacted with PB is considered as a potential active site for drug design. Competitively combination with PA can halt the assembly of RNA polymerase complex, therefore, inhibit the viral replication. Design of new antiviral drugs targeting at PA subunit has important practical significance.This thesis includes the following three sections: A molecular dynamics simulation of the complex containing two zinc finger motifs combined with MM-PBSA/GBSA computations and energy decomposition has been performed. Detailed structure and energy information of the binding site was obtained. And, through the dynamics structure information and the pair interaction analysis, some hot spots of P-TEFb were identified. The results can lay the foundation for further drug discovery.A molecular dynamics simulation of the complex combined with MM-PBSA/GBSA computations and energy decomposition has been performed. And, detailed structure and energy information of the binding pocket was obtained. The binding pocket of CDK9 interacted with Flavopiridol is an important active site for anti-HIV drug design. Therefore, the results can be useful in understanding of the active site and HIV-1 inhibitors design.The virtual screening was performed initial at analysis of interactions between PA and PB1. Some potential inhibitors were obtained through docking 7.8 million small molecules into the binding site of PA. The virtual screening results can provide significant information for anti-H5N1 drug design.