Structure-based design and discovery of small molecule inhibitors of protein-protein interactions

Protein-protein interactions represent a large and important class of targets for human therapeutics. The design of small molecule inhibitors of protein-protein interactions, however, is a challenging area in medicinal chemistry. This dissertation focuses on applying computational methods to design and discover small molecule inhibitors to target two protein-protein interactions, namely the MDM2 - p53 interaction and the XIAP - caspase-9 interaction, respectively.; Using a structure-based de novo design strategy, a class of spiro-oxindole compounds was designed as a new class of small molecule inhibitors of the MDM2-p53 interactions. This study led to one of the most potent, non-peptidic, small molecule inhibitors of the MDM2-p53 interaction discovered to date. Molecular dynamics simulations and free energy calculations have been employed to explore the dynamic behavior of MDM2 in complex with the spiro-oxindole inhibitors and to investigate the contributions of specific chemical groups in the spiro-oxindole inhibitor to binding affinities.; In addition to de novo design, virtual screening was used to discover new small molecule inhibitors of the MDM2-p53 interaction. Novel inhibitors with binding affinity in the nanomolar range were identified. Additional cellular studies demonstrate that one of the most potent hits identified has a mechanism of action consistent with targeting the MDM2-p53 interaction and represents a promising new class of non-peptide inhibitors of the MDM2-p53 interaction.; A virtual screening strategy was also employed to discover novel small molecule inhibitors of the XIAP-caspase 9 interaction. The most potent identified compound binds to XIAP BIR3 with an affinity similar to that of the natural Smac peptide. It was showed that this lead compound inhibits cell growth and induces apoptosis in cancer cells with high levels of XIAP.; Water molecules play an important role in protein-ligand interactions. However their precise contribution to the free-energy of binding is not known. A computational study was carried out to determine the binding free energy of interfacial water molecules in protein-ligand complexes using the double-decoupling free energy simulation method on two HIV-1 protease-inhibitor complexes. This study led to a deeper understanding of several important factors that influence the free energy contributions of interfacial water molecules to protein-ligand binding.