Abstract
There has been a serious outbreak and neurological complication of enterovirus 71 (EV71) infection in Southeast Asia, especially in Malaysia and Taiwan. A large scale hand-foot-and-mouth disease (HFMD) occurred in Taiwan in 1998 in which more than 80 children died of shock syndrome of pulmonary edema/hemorrhage. Since the 1998 epidemic outbreak, EV71 has been isolated throughout the whole island all year long and many fatal cases have been reported. This prompts the need to search and develop more effective anti-EV71 agents. In this thesis, I build a rational method to study the active site of the protein and define the improvement of the inhibitors of EV71 VP1 starting from its single sequence. Firstly, the structure of EV71 capsid protein VP1 has been constructed using a homology modeling and a further structure refinement using the MD simulation technique for Mod1 with the most active ligand lig20 synthesized by Shia et al.17 engulfed is conducted using the SYBYL 6.9.1, InsightII/Discover, and Discover 3 MD simulation programs, respectively. The protein model was validated using some programs such as ERRAT, PROCHECK, PROVE, and PROSA2003. Secondly, the three-dimensional quantitative structure-activity relationship (3D QSAR) techniques, including the SYBYL7.0/CoMFA, SYBYL7.0/CoMSIA, CATALYST4.9, VOLSURF4.1/PCA and PLS programs, has been used by some inhibitors of EV71 VP1 synthesized by Shia et al. (J. Med. Chem. 2002, 45, 1644-1655) in 2002 and Chern et al. (J. Med. Chem. 2004, 14, 5051-5056 ) in 2004. Be sure to discuss the interaction mechanist between the inhibitors and protein residues, the change of binding free energy has been calculated by MD simulation with using single site-directed mutation methods. These studies and projections referred here to identify some important clues for searching or making more potent inhibitors of EV71 VP1 protein to against the infection by EV71.