This project aims to develop new methods and computational tools that will speed structure-based drug- discovery by providing a detailed analysis of hydration structure and thermodynamics in targeted protein binding pockets, and incorporating this information into fast docking algorithms.
Key aims are to extend the evaluation of grid-based inhomogeneous solvation theory (GIST) entropy terms up to second order, develop methods that allow GIST to be applicable to polarizable fields, and exploit empirical data on the patterning of hydrogen bonding sites surrounding bridging water molecules to develop a Pseudo Explicit Water (PEW) method that accounts for the thermodynamic consequences of water-mediated protein-ligand interactions. The extended GIST and PEW methods will be integrated, individually and in combingation, into fast new scoring functions for ligand docking and scoring, for which promising preliminary results are provided in this proposal. Finally, in order to maximize scientific and health impact, software capable of implementing these advances will be packaged, documented and disseminated as part of the freely available, widely used and open source AMBER Tools and DOCK software suites.
Most medications are molecules that work by binding tightly to a specific pocket in the surface of a protein involved in a disease process, and thus blocking the protein?s disease-related function. This project aims to develop advanced computational methods and software that will speed the discovery of new medications by helping scientists design or discover molecules that will bind tightly to a targeted protein. The methods and software developed here will be fully documented and freely distributed for general use.
