Investigating the inhibitors of hTMPK via Computer-Aided drug design
| Autor: | Ting-Wei Tsai, 蔡庭瑋 |
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| Rok vydání: | 2017 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 105 Human thymidylate kinase (hTMPK) plays a central role in the biosynthesis of deoxythymidine triphosphate. In both de novo pathway and salvage pathway, it catalyzes the reversible phosphoryl transfer between deoxyadenosine triphosphate and deoxythymidine monophosphate to form deoxyadenosine diphosphate and deoxythymidine diphosphate. This process is indispensable in supplying precursors for DNA synthesis. In literatures, the inhibition of hTMPK in tumor cells leads to cell death. A hTMPK inhibitor, YMU1, was screened out from series of compounds. YMU1 can inhibit the activity of hTMPK through disrupting the binding pocket of ATP to hTMPK. Previous studies have shown that when YMU1 locating in the B site which consists of the LID region and P-loop, can affect enzymatic activity. In present study, we perform molecular docking to predict the binding modes of the YMU1 derivatives to hTMPK. Then, molecular dynamics simulations methods were carried out to obtain thermodynamic data. The hTMPK crystal structure was provided by Prof. N.-L Chan (NTU), and the derivatives of YMU1 (JMF3914, JMF4073, JMF3970, JMF3507, JMF3791, JMF4205) were provided by Prof. J. M. Fang (NTU). Four sites (A, B, C and D) have been observed. A site locates at the top of LID region. Our results show that four binding sites (A, B, C and D) are observed. B position and D position are the more likely binding sites. Compare to YMU1, YMU1’s derivatives with better ability of inhibition might bind to position B and position D to get a better ability of inhibition and combine free energy results. According to the results of molecular dynamics simulation, new drugs which can combine to the B site or even binding to B and D sites in the same time can be made. In our research, the modeled new drugs have great binding free energy results and this shows that simulation is a feasible way for the design of inhibitors of human thymidylate kinase. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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