When measured sensibly, there is a direct and exploitable relationship between protein binding site similarity and similarity among cognate ligands. Using methods that depend on local surface shape and electrostatic comparisons, it is possible to correctly link proteins with little to no evolutionary relationship. Similarly, it is possible to correctly link ligands that exhibit little to no topological similarity. By combining these techniques, it is possible to predict off-target biological effects and to identify suprising examples of pharmacological crosstalk. By exploiting the natural complementarity between protein and ligand similarity at their interacting surfaces, it is possible to derive quantitatively predictive physical models of protein binding sites using ligand structure and activity data. Specific examples of extrapolative predictions will be shown in the context of applications in off-target identification, lead discovery, and lead optimization.

Duality of protein binding site similarity and cognate ligand similarity

254th National Meeting (2017)

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