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

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• 作者：Brett R. Beno ; Kap-Sun Yeung ; Michael D. Bartberger ; Lewis D. Pennington ; Nicholas A. Meanwell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：June 11, 2015
• 年：2015
• 卷：58
• 期：11
• 页码：4383-4438
• 全文大小：2803K
• ISSN：1520-4804

文摘

Electron deficient, bivalent sulfur atoms have two areas of positive electrostatic potential, a consequence of the low-lying 蟽* orbitals of the C鈥揝 bond that are available for interaction with electron donors including oxygen and nitrogen atoms and, possibly, 蟺-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 蟽* 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鈥揝 蟽* orbitals and proteins are illustrated.