| The design and optimization of chemotherapeutic molecules through molecular modeling is a rapidly growing aspect of chemotherapeutic drug design. The recent increase in computer power and accompanying decrease in the cost of hardware has led to the wide use of computational chemistry in the development of new drugs. In addition, virtual screening of libraries of compounds also aids in the rapid development of new drugs. In that regard, three computational drug design projects plus a project involving the synthesis of potential inhibitors compile the research presented herein.;In the first project, molecular mechanics simulations were used to model a series of potential inhibitors in the binding site of S-adenosylhomocysteine hydrolase (SAHase), a biologically significant enzyme that is an essential part in the methylation pathway. The modeled compounds are isomers of adenosine possessing the glycosidic linkage at the N3-position instead of the N9-position found in normal purine nucleosides. All binding energies obtained for the SAHase enzyme-ligand complexes were compared to the most potent inhibitor reported to date, carbocyclic 4',5'-enyl-3-deazaadenosine.;In the second project, another series of molecules was modeled using molecular mechanics simulations, and as before, these molecules were also modeled in the binding site of SAHase. This series focuses on using flexible nucleosides as bioprobes to investigate the implications of flexibility on the enzyme. These analogues have their purine bases separated into their imidazole and pyrimidine components, but are connected together by a single carbon-carbon bond. This allows rotation between the two pieces of the nucleobase thereby increasing the overall flexibility of the molecule.;In the third project, molecular dynamics calculations were performed on expanded purine nucleotides in a modified DNA strand. The expanded adenosine and guanosine bases possess either a furan, pyrrole or thiophene spacer ring in between the normal imidazole and pyrimidine rings of the purine scaffold. The calculations were performed on 10- and 20-mer strands in order to probe the stability and parameters of the strands.;The final project focuses on the synthesis of a series of chlorinated 3-deazaadenine analogues that were designed as potential inhibitors of SAHase. This SAR study systematically placed various combinations of chlorine atoms on a 3-deazaadenine base in the 2, 6 and 8 positions to determine the effect of chlorination on a known inhibitor. |
