A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design.
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.
†Department of Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway Wallingford Connecticut 06492, United States.
Brett R
BR
Beno
‡Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway Wallingford Connecticut 06492, United States.
Kap-Sun
KS
Yeung
§Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive Thousand Oaks California 91320, United States.
Michael D
MD
Bartberger
§Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive Thousand Oaks California 91320, United States.
Lewis D
LD
Pennington
‡Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway Wallingford Connecticut 06492, United States.
Nicholas A
NA
Meanwell
D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D013455:Sulfur / Q000737:chemistry* / Q000378:metabolism*
D011506:Proteins; D013455:Sulfur