Development and Application of Molecular Modeling Methods for Structure-Based Drug Discovery

Abstract: Molecular modeling is increasingly being integrated into the drug discovery process. Although computational methods are already an essential part of the process today, these techniques have vast potential to evolve and refine drug design in the future. The integration of modeling is further catalyzed by the rapidly growing computational power available to both academia and pharmaceutical companies. These resources extend the reach of the computational methods to new time scales in physics-based simulations of biomolecular systems and increase the number of molecules that is possible to dock to a receptor by several orders of magnitude. However, there is also a need for further development of methods that utilize the increased computational power to increase the level of detail in modeling of molecular interactions. The work presented in this thesis has contributed to method development in two different areas and demonstrated how virtual screening can be applied to identify ligands of proteins. The first main project investigated modeling of ordered water molecules in protein binding sites to understand the role of water in molecular recognition and the impact of ligands on hydration networks. In a second project, an approach for discovery and optimization of fragment-sized ligands based on virtual screening was developed and used to identify inhibitors of a cancer drug target. Finally, molecular docking was applied to assess proposed substrates of cytochrome b561, a recently crystallized membrane protein.