Computational studies toward the design and synthesis of novel inhibitor compounds

K_i/ΔG predictive minireceptor for the oxytocin receptor was constructed. The purpose of the study was to identify novel oxytocin antagonist lead compounds. The minireceptor with excellent correlation was constructed around the pharmacophore and provides K_i/ΔG for compounds with unknown binding constants. The minireceptor was also able to account for receptor selectivity. The minireceptor was used to make predictions on several new structures. Structures with appropriate predicted binding affinity were submitted for biological activity testing.; Computational studies toward the design of novel Human Cytomegalovirus (HCMV) serine proteases are presented. An atomic level non-covalent HCMV serine protease inhibitor complex was developed from a covalently modified HCMV serine protease inhibitor complex. Molecular dynamics simulation was used for structure refinement. The atomic level non-covalent model was shown to be in good agreement with other x-ray structures of non-covalent serine protease inhibitor complexes. To gain further understanding of the fundamental aspects HCMV serine protease, the reaction barrier for the HCMV serine protease catalyzed hydrolysis was studied with ab initio and DFT methods. It was shown that the reaction barrier was higher for HCMV serine protease than classic serine protease such as elastase. The third residue of the catalytic triad in HCMV serine protease, histidine, was shown to have a smaller effect in lowering the reaction barrier compared to classic serine proteases where the third residue is aspartate.