3D matched pairs: integrating ligand- and structure-based knowledge for ligand design and receptor annotation.

We describe an extension to the matched molecular pairs approach that merges pairwise activity differences with three-dimensional contextual information derived from X-ray crystal structures and binding pose predictions. The incorporation of 3D binding poses allows the direct comparison of structural changes to diverse chemotypes in particular binding pockets, facilitating the transfer of SAR from one series to another. Integrating matched pair data with the receptor structure can also highlight activity patterns within the binding site--for example, "hot spot" regions can be visualized where changes in the ligand structure are more likely to impact activity. The method is illustrated using P38α structural and activity data to generate novel hybrid ligands, identify SAR transfer networks, and annotate the receptor binding site.

Conserved core substructures in the overlay of protein-ligand complexes.

The method of conserved core substructure matching (CSM) for the overlay of protein-ligand complexes is described. The method relies upon distance geometry to align structurally similar substructures without regard to sequence similarity onto substructures from a reference protein empirically selected to include key determinants of binding site location and geometry. The error in ligand position is reduced in reoriented ensembles generated with CSM when compared to other overlay methods. Since CSM can only succeed when the selected core substructure is geometrically conserved, misalignments only rarely occur. The method may be applied to reliably overlay large numbers of protein-ligand complexes in a way that optimizes ligand position at a specific binding site or subsite or to align structures from large and diverse protein families where the conserved binding site is localized to only a small portion of either protein. Core substructures may be complex and must be chosen with care. We have created a database of empirically selected core substructures to demonstrate the utility of CSM alignment of ligand binding sites in important drug targets. A Web-based interface can be used to apply CSM to align large collections of protein-ligand complexes for use in drug design using these substructures or to evaluate the use of alternative core substructures that may then be shared with the larger user community. Examples show the benefit of CSM in the practice of structure-based drug design.