Molecular Dynamics Simulation of Several Protein Kinase A - Inhibitor Complexs : Binding Energy Calculation

• Main Author: 陳鼎欣
• Other Authors: 孫英傑
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/13807989834610584972

碩士 === 國立臺灣師範大學 === 化學系 === 98 === Protein kinase A plays significant role in a number of signaling pathways in cell, and is thought to be a potential drug target for treatments of several diseases by inhibiting its kinase activity. In the present study, we aimed to use molecular dynamics simulation method to aid in design of PKA inhibitors. We selected 4 ligand-PKA complexes, in which their ligands are analogous, from Protein data bank with available IC50 values, MM/PB(GB)SA was employed to investigate the binding between ligand and PKA. The calculated binding energies are in good accord with the available IC50 values of examined complexes except one. The calculated results were analyzed and discussed to aid in understanding which functional group substitutions can enhance the binding affinity. Based on these results,we further designed 5 new ligands to predict their binding affinities. The calculated results suggest the fillowing points to change the functional groups: (1) Adding a methyl group at the R1 or R3 position (see Figure in the text) of the single ring in the ligand can enhance the binding affinity. The van der Waals interaction is the main contributor in the total binding energy . (2) Adding a hydroxyl group at R5 position of the singl ring gave stable hydrogen bonds with the LYS 168 and ASP 184, increasing the binding affinity. These results together with the analysis above should be able to aid in design of PKA inhibitors analogous to the ligands investigated in the present study.