This dissertation, studies two specific topics related to the research of computer-aided drug design(CADD) by employing the molecular simulations approach, that of protein drugs and that of small agents. These results can help drug designers to improve their products for treating special diseases. This work is divided into two parts:
Protein drugs:
Potential of mean force of the hepatitis C virus core protein¡Vmonoclonal 19D9D6 antibody interaction: Antigen-antibody interactions are critical for understanding antigen-antibody associations in immunology. To shed further light on this question, we studied a dissociation of the 19D9D6-HCV core protein antibody complex structure. However, forced separations in single molecule experiments are difficult, and therefore molecular simulation techniques were applied in our study. The stretching, that is, the distance between the centre of mass of the HCV core protein and the 19D9D6 antibody, has been studied using the potential of mean force calculations based on molecular dynamics and the explicit water model. Our simulations indicate that the 7 residues Gly70, Gly72, Gly134, Gly158, Glu219, Gln221 and Tyr314, the interaction region (antibody), and the 14 interprotein molecular hydrogen bonds might play important roles in the antigen-antibody interaction, and this finding may be useful for protein engineering of this antigen-antibody structure. In addition, the 3 residues Gly134, Gly158 and Tyr314 might be more important in the development of bioactive antibody analogues.
Potential of mean force for syrian hamster prion epitope protein - monoclonal fab 3f4 antibody interaction studies: Simulating antigen-antibody interactions is crucial for understanding antigen-antibody associations in immunology. To shed further light into this question, we study a dissociation of syrian hamster prion epitope protein-fab3f4 antibody complex structure. The stretching (the distance between the center of mass of the prion epitope protein and the fab3f4 antibody) have been studied using potential of mean force (PMF) calculations based on molecular dynamics (MD) and implicit water model. For the complex structure, there are four important intermediates and two inter protein molecular hydrogen bonds in the stretching process. Inclusion of our simulations may help to understand the binding mechanics of the complex structure and will be an important consideration in design of antibodies against the prion disease.
Potential of mean force for human lysozyme - camelid vhh hl6 antibody interaction studies: Calculating antigen-antibody interaction energies is crucial for understanding antigen-antibody associations in immunology. To shed further light into this equation, we study a separation of human lysozyme-camelid vhh hl6 antibody (cAb-HuL6) complex. The c-terminal end-to-end stretching of the lysozyme-antibody complex structures have been studied using potential of mean force (PMF) calculations based on molecular dynamics (MD) and explicit water model. For the lysozyme-antibody complex, there are six important intermediates in the c-terminal extensions process. Inclusion of our simulations may help to understand the binding mechanics of lysozym- cAb-HuL6 antibody complex.
Small agents:
Predictions of binding for dopamine D2 receptor antagonists by the SIE method: The control of tetralindiol derivative antagonists released through the inhibition of dopamine D2 receptors has been identified as a potential target for the treatment of schizophrenia. We employed molecular dynamics simulation techniques to identify the predicted D2 receptor structure. Homology models of the protein were developed on the basis of crystal structures of four receptor crystals. Compound docking revealed the possible binding mode. In addition, the docking analyses results indicate that five residues (Asp72, Val73, Cys76, Leu183, and Phe187) were responsible for the selectivity of the tetralindiol derivatives. Our molecular dynamics simulations were applied in combination with the solvated interaction energies (SIE) technique to predict the compounds' docking modes in the binding pocket of the D2 receptor. The simulations revealed satisfactory correlations between the calculated and experimental binding affinities of all seven tetralindiol derivative antagonists, as indicated by the obtained R2 value of 0.815.
Combining homology modeling, docking, and molecular dynamics to predict the binding modes of oseltamivir, zanamivir, and Chinese natural herb products with the neuramindase of the H1N1 influenza A virus: The neuraminidase of the influenza virus is the target of the anti-flu drugs oseltamivir and zanamivir. Clinical practices show that zanamivir and oseltamivir are effective to treat the 2009 H1N1 influenza virus. Herein, we report the findings of molecular simulations for zanamivir, oseltamivir, and Chinese natural herb products with the neuramindase of the 2009 H1N1 influenza. Our approach theoretically suggests that the Glu278 residue is responsible for the neuramindase of the 2009 influenza drug selectivity.
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0629111-133823 |
| Date | 29 June 2011 |
| Creators | Wang, Yeng-Tsneg |
| Contributors | Ming-Yu Kuo, Chao-Ming Chiang, Jen-wei Yu, Cheng-Lung Chen, Ming-Jung Wu |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0629111-133823 |
| Rights | not_available, Copyright information available at source archive |
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