S···O and S···N Sulfur Bonding Interactions in Protein–Ligand Complexes: Empirical Considerations and Scoring Function

Sulfur
bonding interactions between organosulfur compounds and
proteins were examined using crystal structures deposited to-date
in the PDB. The data was analyzed as a function of sulfur-σ-hole-bonding
(i.e., sulfur bonds) to main chain Lewis bases, viz. oxygen and nitrogen
atoms of the backbone amide linkages. The analyses also included an
examination of sulfur bonding to side chain Lewis bases (O, N, and
S) and to the “non-classical” Lewis bases present in
electron-rich aromatic amino acids as-well-as to donor–acceptor
bond angle distributions. The interactions analyzed included those
restricted to the sum of van der Waals radii of the respective atoms
or to a distance of 4 Å. The surveyed data revealed that sulfur
bonding tendencies (C–S–C bond angles) were impacted
not only by steric effects but perhaps also by enthalpic features
present in both the donor and acceptor participants. This knowledge
is not only of fundamental interest but is also important in terms
of materials and drug-design involving moieties incorporating the
sulfur atom. Additionally, a new empirical scoring function was developed
to address the anisotropy of sulfur in protein–ligand interactions.
This newly developed scoring function is incorporated into AutoDock
Vina molecular docking program and is valuable for modeling and drug
design.