Carboranes as Hydrophobic Pharmacophores

Abstract

A pharmacophore is a partial structure in which important functional groups and hydrophobic structure are arranged in suitable positions for binding to a receptor [1]. Typically, hydrophilic functional groups of the pharmacophore interact with the receptor by hydrogen bonding and/or ionic bonding, and the hydrophobic structure interacts with a hydrophobic surface of the receptor. While hydrogen bonding plays a key role in specific ligand–receptor recognition, the hydrophobic interaction between receptor and drug molecule is especially important in determining the binding affinity. The difference of binding constants between a ligand having a suitable hydrophobic group and a ligand without such a group can be as large as 1000‐fold. In medicinal drug design, the hydrophobic structures are often composed of aromatic and heteroaromatic rings, which also play a role in fixing the arrangement of functional groups appropriately for binding to the receptor. On the other hand, three‐dimensional hydrophobic structures are not yet widely used in drug design, even though they could be well suited for interaction with the three‐dimensional hydrophobic binding pockets of receptors. It is noteworthy that various steroid hormones target distinct steroid hormone receptors owing to differences of functionalization of the hydrophobic steroidal skeleton. The binding of the natural ligand 17β‐estradiol to human estrogen receptor‐α (ERα) is illustrated in Figure 1.1.1 as an example. The large number of steroid hormones may be a consequence of evolutionary diversification of the functions of the steroidal skeleton. In this context, we aimed to establish a new three‐dimensional hydrophobic skeletal structure for medicinal drug design. Carboranes as Hydrophobic Pharmacophores: Applications for Design of Nuclear Receptor Ligands