Thesis (Ph.D.)--Chulalongkorn University, 2013

NS3/4A protease and neuraminidase (NA) enzymes play a crucial role to cleave the peptide bond and glycosidic bond during the replication process of hepatitis C and influenza viruses, respectively. Thus, NS3/4A and both wild-type (WT) and H274Y mutant of NA subtypes H5N1 and pH1N1 were focused. Initially, NS3/4A binding to the current inhibitors (boceprevir, telaprevir, danoprevir as well as NA bound with laninamivir were studied in order to investigate their binding pattern and ligand-target interactions as well as the binding efficiency using the conventional molecular dynamics (MD) simulation. The per-residue decomposition energy was calculated by molecular mechanics (MM)/generalized Born surface area (GBSA) indicating that the residues 41-43, 57, 81, 136-139, 155-159 and 168 of NS3/4A and 118-119, 151-152, 178, 224, 227, 276, 292 and 371 of all 4 NAs are the key binding residues. Van der Waals interaction is the main contribution to NS3/4A protease inhibitors binding, whereas the main contribution stabilized laninamivir binding is electrostatic interaction. Since some side effects have been observed in patients who treated by approved anti-HCV drugs, the new potent NS3/4A inhibitors have been needed. Therefore the potent inhibitors against NS3/4A were searched from the collected 40 ZINC ligands using steered MD technique based on the hypothesis that the high rupture force is needed for the high efficiency ligand. It was found that 9 top-hit compounds were probably good as or better than the 4 current NS3/4A inhibitors. Based on the SCC-DFTB/MM MD simulation, the acylation step of NS3/4A binding to beceprevir and telaprevir was occurred in the concerted manner as same as the native substrates which their energy barriers for the backward reaction of both systems were 19-23 kcal/mol approximately. This result is somewhat similar to the experimental data.