The goal of this project is to develop the use of wide-angle x-ray solution scattering (WAXS) as a routine screening tool for detection of functional interactions between proteins of therapeutic interest and small molecule ligands for the purposes of drug discovery and development. The process of lead discovery presents an early and significant bottleneck in the process of pharmaceutical drug design and slows the ultimate development of new therapeutic treatments. WAXS constitutes a new and powerful tool to impact this process. The technique is target-general, meaning that a single, standard protocol for the collection of WAXS data can be applied to virtually any protein. The protein targets need only be aqueous soluble at moderate concentration to make them amenable to these studies and no specialized sample handling or preparation is necessary. To adapt this approach to moderate throughput commercial service, we propose to automate both the data collection and the data analysis processes to make them as rapid and user-friendly as possible.
The specific aims are (1) to develop automated sample handling hardware and associated control systems by constructing a portable, wide-angle camera with robotic control of specimen handling;(2) to develop a software package to automate downstream data processing and analysis by updating and improving currently utilized software and incorporating these processes into a user- friendly, comprehensive interface;and (3) to conduct a double-blind proof of concept test of the method by screening a library of 50-75 compounds, prepared by a commercial Pharmaceutical Company, against 3-4 pharmaceutically relevant protein targets and statistically evaluating the ability of the technique to distinguish the known target binders from other compounds in the library.
This project will develop for commercialization a new technique having high potential to impact the pharmaceutical lead discovery process. Decreased development of novel tools to impact this area has resulted in continual slowing of the process of drug discovery and in stagnation of medicinal chemistry innovation meaning that fewer effective new disease therapies are available to the public.
