Norman Hascoe Distinguished Lecture Series

The starting point for structure-based drug design (SBDD) efforts is a high quality structural model obtained using X-ray crystallography or NMR spectroscopic techniques. Recently, it has become clear that many available protein/ligand complexes have structural inconsistencies that limit their usefulness in developing and validating SBDD tools like docking and scoring methodologies. In most instances classical tools are used as structural surrogates in X-ray and NMR refinement protocols in order to improve the parameter to observation ratio realized from these experimental techniques. While classical approaches are useful structural surrogates, they do suffer from a number of issues that affect their performance including: electrostatic modeling, parameter defects and missing parameters. The way in which these issues can be mitigated is to use more robust structural theories like quantum mechanical (QM) methods, which have had a tremendous impact on our understanding of “small” chemical and biological systems. In this presentation we will focus on some of the first applications of ab initio QM methods to refine protein/ligand complexes for use in SBDD applications. In our first example, we will describe the use of computational NMR spectroscopy tools to place or “pose” ligands in the active site of a protein, while in the second example we will discuss the use of QM in X-ray structure refinement. Finally, we will briefly summarize our vision of the future application of quantum chemistry to structure refinement as well as SBDD.