| The cyclohexyl fragment is a popular building in both natural and synthetic drugs, serving as either the core structure or as part of aperipheral side chain. The cyclohexyl group may function as a bioisostere for the t-butyl group for a deeper hydrophilic pocket on target protein. As a rigid version of floppy alkyl chain, the cyclohexyl replacement reduces entropy and may offer better affinity. As a bioisotere for the flat phenyl group, cyclohexyl substituent has the advantage of being three dimensional, which potentially offers more contact points with target protein. This concept has been proven in the discovery of venetoclax(Venclexta). In addition, the cyclohexenyl motif is a metabolically more stable bioisostere for furanose and this concept has been demonstrated by the success of oseltamivir (Tamiflu).
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