title: Evaluating the potential of halogen bonding in molecular design: automated scaffold decoration using the new scoring function XBScore.
abstract: We present a QM-derived empirical scoring function for the interaction between aromatic halogenated ligands and the carbonyl oxygen atom of the protein backbone. Applying this scoring function, we developed an algorithm that evaluates the potential of protein-bound ligands to form favorable halogen-bonding contacts upon scaffold decoration with chlorine, bromine, or iodine. Full recovery of all existing halogen bonds in the PDB involving the protein backbone was achieved with our protocol. Interestingly, the potential for introducing halogen bonds through scaffold decoration of unsubstituted aromatic carbon atoms appears to easily match the number of previously known halogen bonds. Our approach can thus be used as a blueprint for integration of halogen bonding into general empirical scoring functions, which at present ignore this interaction. Most importantly, we were able to identify a substantial number of protein-ligand complexes where the benefits and challenges of introducing a halogen bond by molecular design can be studied experimentally.
authors: Laboratory for Molecular Design and Pharmaceutical Biophysics, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors: Markus O
authors: MO
authors: Zimmermann
authors: Laboratory for Molecular Design and Pharmaceutical Biophysics, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors: Andreas
authors: A
authors: Lange
authors: Laboratory for Molecular Design and Pharmaceutical Biophysics, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors: Frank M
authors: FM
authors: Boeckler
mesh_terms: D057225:Data Mining / Q000379:methods*; D030562:Databases, Protein; D055808:Drug Discovery / Q000379:methods*; D006219:Halogens / Q000737:chemistry*; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D010100:Oxygen / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*; D015203:Reproducibility of Results
chemical_list: D006219:Halogens; D008024:Ligands; D011506:Proteins; D010100:Oxygen