Enhancement and Deployment of the Quantum Mechanical X-ray Refinement Model

DESCRIPTION (provided by applicant): Combined Improving human health by enabling the development of drugs faster and cheaper is an important part of the NIH mission. This is partially achieved by introducing and constantly improving enabling technologies. One such technology is structure based drug design. Determining the structure of a small molecule (drug candidate or lead compound) to a biological receptor (protein implicated in disease) is a necessary step in this methodology. The dominant experimental approach used to achieve this goal is X-ray crystallography, while nuclear magnetic resonance (NMR) plays a lesser role. X-ray techniques provide astounding insights into the structure of protein-ligand complexes, but can be hampered by the resolution to w hich a crystal diffracts and the refinement process can be hampered by the lack of good potentials for novel small molecule compounds. The aim of the proposed research is to extend and further validate our linear-scaling semiempirical quantum mechanical mo lecular mechanical X-ray refinement approach (QM/MMXray). In general the limits of applicability will be researched and in particular the following question will be posed in the Phase I project: Can QM/MMX-ray provide better structure quality for a protein -ligand complex as measured by various crystallographic metrics (R, Rfree, ?A-weighted Fourier difference maps, etc.)? Upon successful completion of the Phase I project we will further enhance and extend the QM/MMXray method and produce commercial quality code. If this approach proves robust enough it is anticipated that the use of QM/MMXray in structure-based design efforts will be enhanced and the Xray tool and service market size can be further expanded. Significantly, the tool-box of structure based dru g design will gain an important new method which will enable drug development for targets inaccessible to today's mainstream drug discovery paradigm. Thus, in the near future important underserved diseases can be targeted more efficiently. PUBLIC HE ALTH RELEVANCE: The successful completion of the Fast-Track STTR grant will have a major impact on improving human health. It will improve the quality of protein structures, facilitate the understanding of biomolecular dynamics and will provide higher qual ity structural insights into protein/ligand (drug) interactions which will enhance our ability to rationally design novel therapeutics for human diseases.