Analysis of water stability and positions in a ligand-protein complex informed the design of novel ligands for a customer target. This led to new active chemistry that the customer went on to patent.
A Cresset Discovery Services customer had identified a novel target with a natural ligand and
The customer used this information to develop analogous synthetic compounds and example molecules. They asked us to work with them again to computationally align the example molecules and prioritize them for synthesis.
We carried out an initial alignment and then
The PDB had some crystal structures of related proteins, but not of the target of interest. We studied the available protein data to learn as much as possible about the binding pocket, paying particular attention to the positions and stability of the water molecules. This led to us putting forward the hypothesis that an important part of the ligand interaction included the stabilization of water.
Based on this hypothesis we prioritized the molecules that bridged the observed gap between the natural ligand and the target while also stabilizing the free waters.
Water analysis was carried out by manually superimposing multiple crystal structures, viewing the crystallographic waters that clustered together, and mapping on their temperature factors. This process allowed us to determine the importance of each water molecule in the solvation sphere around the ligand and protein pocket. With the advent of the new 3D-RISM method in
Based on our equivalent ‘hands-on’ analysis, we worked with the customer to choose the best candidates for synthesis. These newly-designed ligands resulted in new active chemistry for the customer that was valuable enough for them to patent.
The position and energetics of water molecules in and around the active site
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