All protein-ligand binding interactions occur in an aqueous environment, therefore predicting the effects of solvent molecules within the binding site is a necessary step in understanding binding affinity. However, the interactions of protein and ligand together with water molecules can have complex and non-obvious effects, which can complicate and obfuscate a lead-optimization campaign. SZMAP is OpenEye’s application to help modelers and medicinal chemists understand the role of water in molecular interactions such as ligand binding. Using water as a lens, SZMAP can provide the user with insight on critical features of a binding site, predict where and how neighboring waters can influence binding of a ligand, or generate ligand modification hypotheses designed to better exploit specific regions on a binding site. The semi-continuum [1, 2] approach used in SZMAP combines one explicit water molecule with robust continuum solvent methods [3], classical statistical mechanics, and thorough sampling plus the ability to analyze specific water orientations.
Integrated into SZMAP is Gameplan, a unique approach to ligand modification/optimization based on the energetics of water at points in a protein binding site close to the ligand of interest. Gameplan provides easy to interpret suggestions for manipulations of a molecular scaffold or additions/extensions to that scaffold to improve binding affinity using an understanding of both the enthalpic and the entropic contributions to water stability.
For more detailed information on SZMAP, check out the links below:
SZMAP and Gameplan are able to make good use of multiple processors to speed calculations on both single computers and computer networks. Significant speedups are possible for a calculation that took close to 3 hours on one CPU with the previous version of SZMAP.