A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design

TLDR

Electron‑deficient sulfur atoms possess two positive electrostatic regions from low‑lying σ* orbitals, making intramolecular interactions the most common way to modulate molecular conformation, yet this effect remains underappreciated in medicinal chemistry. This Perspective reviews the theoretical basis of sulfur σ* orbital interactions and demonstrates their significance for drug design and organic synthesis. The authors examine how sulfur interactions influence protein structure and function, highlighting rare intermolecular contacts between ligand C–S σ* orbitals and proteins.

Abstract

Electron deficient, bivalent sulfur atoms have two areas of positive electrostatic potential, a consequence of the low-lying σ* orbitals of the C–S bond that are available for interaction with electron donors including oxygen and nitrogen atoms and, possibly, π-systems. Intramolecular interactions are by far the most common manifestation of this effect, which offers a means of modulating the conformational preferences of a molecule. Although a well-documented phenomenon, a priori applications in drug design are relatively sparse and this interaction, which is often isosteric with an intramolecular hydrogen-bonding interaction, appears to be underappreciated by the medicinal chemistry community. In this Perspective, we discuss the theoretical basis for sulfur σ* orbital interactions and illustrate their importance in the context of drug design and organic synthesis. The role of sulfur interactions in protein structure and function is discussed and although relatively rare, intermolecular interactions between ligand C–S σ* orbitals and proteins are illustrated.