Improvements in the sensitivity of 2D IR measurements by edge-pixel referencing, model fitting, and signal enhancement methods

The process of modern drug discovery often starts with one target: a defective protein responsible for a genetic disease. Once known, a search ensues for drug candidates that fix the broken protein, and the remaining process consists of testing and clinical trials. The research of this dissertation is concerned with the search step, where chemists screen thousands of compounds against the broken protein. Modern screening methods can quickly see if a compound interacts with a protein, but chemists spend extra time and resources figuring out which of those interacting compounds actually fix the protein. As a result, screening is not very selective and very few drug candidates remain after additional testing.

Two-Dimensional Infrared Spectroscopy (2D IR) is a powerful tool that can measure if a compound changes particular movements of a protein that relate to whether the protein is working as it should. Therefore, the potential exists for 2D IR to speed up high throughput screening as a more selective tool. The purpose of this research is to increase the sensitivity of 2D IR to enable it as a rapid screening tool for drug candidates. Beyond the potential value of enabling a faster screening tool for drug discovery, the results of this research may enable a wide variety of experiments that, until now, have fallen out of reach for the 2D IR community.