May disordered protein cause serious drug side effect?

•We characterize the structural properties of sleep-related receptors and complex.•Computational prediction shows that they share a disorder property.•Failures of drug design might highly relate to the structural disorder properties.

Insomnia is a self-reported disease where patients lose their ability to initiate and maintain sleep, leading to daytime performance impairment. Several drug targets to ameliorate insomnia symptoms have been discovered; however, these drug targets lead to serious side effects. Thus, we characterize the structural properties of these sleep-related receptors and the clock complex and discuss a possible drug design that will reduce side effects. Computational prediction shows that disordered property is shared. Over 30% of the structure of CLOCK, PER1/2/3, BMAL-1, muscarinic acetylcholine receptor-M1, melatonin receptor and casein kinase I are structurally disordered (the remaining proteins represent <30%). Investigations support the principle that the failures of insomnia drugs might be closely related to the protein architecture.