In structure-based design the accurate prediction of the affinity change of ligands with newly designed polar protein-ligand interactions remains a challenge. This is caused by sometimes non-obvious (de)solvation effects that take place during complex formation and geometric requirements for productive polar interactions that are often more stringent compared to apolar contacts. To further increase our understanding of favorable polar interactions and their preferred geometries we have derived quantitative interaction propensities for different functional groups using statistical analyses of crystal structures from the Protein Data Bank. Our approach is based on a line-of-sight analysis introduced earlier by Taylor (DOI: 10.1039/c4ce00452c), which avoids the counting of confounding secondary interactions. We will present statistically preferred polar interaction partners and their geometries, with a focus on functional groups with large dipole moments.<br/>In the second part of the presentation, we will present case studies from internal PDE10 and Cathepsin L projects where different types of polar interactions were refined during hit optimization.

Polar protein-ligand interactions: Statistical significance and use in structure-guided drug design

255th National Meeting (2018)

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