Project Summary This project aims to develop new methods and computational tools that will speed structure-based drug- discovery and apply these methods to identify new lead drug candidates for the mu-opioid receptor and SARS- CoV-2 main proteases. This will be accomplished by providing a detailed analysis of hydration structure and thermodynamics in targeted protein binding pockets then incorporating this information into docking and water-based pharmacophore virtual screens. Key aims are to develop analysis tools that characterize and map out solvation on the surfaces of drug target then utilize these solvation structural and thermodynamic maps to improve computational methods of binding pocket druggability, virtual screening of purchasable compound databases, and rational lead modification. Preliminary results for a new method of virtual screening that combines constructing pharmacophores based on water-protein interactions with ROCS fast shape and pattern matching show the method is greater than 3 orders of magnitude faster than computational docking.