Characterization of Protein–Ligand Chalcogen Bonds: Insights from Database Survey and Quantum Mechanics Calculations

Chalcogen
bonds (ChBs) are essential noncovalent interactions
in
biological systems and drug molecules, playing a key role in stabilizing
protein structures and determining the bound conformations of drugs.
While previous studies on ChBs in biological systems have primarily
focused on interactions between residues and within drug molecules,
systematic investigations into the characteristics of ChBs between
proteins and ligands remain limited. This study systematically explores
ChBs between proteins and sulfur-containing ligands using comprehensive
database analyses and precise quantum mechanics (QM) calculations.
The findings reveal the persistent prevalence of sulfur throughout
the drug development process, underscoring the importance of considering
sulfur’s role in fragment-based drug design. A survey of the
Protein Data Bank (PDB) identified specific preferences in distance,
angle, and backbone/side chain interactions for ChBs within protein–ligand
complexes, offering valuable insights for structure-based drug design.
Furthermore, QM calculations demonstrate that protein–ligand
ChBs are characterized by electrostatic complementarity, dispersion,
and inter/intramolecular charge transfer. This systematic investigation
substantially advances our understanding of protein–ligand
ChBs in biological systems.