May disordered protein cause serious drug side effect?


Insomnia is a sleep disorder characterized by the inability to fall asleep, in 2011 the 12-20% of the general adult population suffer insomnia, with more predisposition in the USA. The abnormal sleep cycle results in other symptoms like, lack of motivation, mood disturbances, loss of memory, tiredness, deficiency of energy, headaches and some gastrointestinal disorders.
The most common treatment for insomnia is medication with benzodiazepine and non-benzodiazepine drugs. The benzodiazepine drugs enhance the effect of the GABA (g amino butyric acid) at GABAA receptor, resulting in a sedative, hypnotic, muscle relaxing, sleeping inducing and anxiolytic effects. Non benzodiazepine drugs include Non-benzodiazepine drugs include zolpidem tartrate (Ambien®), sodium butabarbital (Butisol®) and eszopiclone (Lunesta®). The major disadvantages of these drugs are the multiple side effects: tolerance, dependence and memory impairment.
In the article by Weng and Calvin (http://www.sciencedirect.com/science/article/pii/S1359644613003875) they proposed a possible drug design strategy that might reduce the side effects by considering disordered proteins related with insomnia.
The sleep-related protein/receptor can be classified into the clock complex and the hypnotic-related receptor (HRR). The clock complex controls the circadian rhythm activity; genetic mutations in this complex had showed dysfunctions in the perception of sunset and sunrise, leading to sleep disorder. This complex is formed by several proteins, like BMAL-1, CLOCK, CRY1/2, CKI/II and PER1/2/3.
The HRR, includes dopamine receptors (D2/D3), GABAA, histamine receptor (H1/H2), melatonin receptor, muscarinic receptor M1 and orexin receptor 1/2.
In the study they analyzed the structural properties of clock complex and HRR by computational techniques and they found that the majority of the clock complex proteins share a highly disordered property, located in the middle of the sequence, implicated the flexibility of the whole complex. Over the 30% of CLOCK, PER1/2/3, BMAL-1, M1, melatonin receptor and CKI are disordered, the percentage of structural disorder in HRR is much lower that the clock complex.

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The clock complex showed more disordered rate in the middle of the sequence, implicated the flexibility of the whole complex. They suggest HRR it might be a better drug target for new insomnia therapies due to the small possibility of affecting the flexibility and stability of the complex. They mention that some investigators had give strong evidence of structure lead to side effects, because the there are limited binding sites in nature.
They suggest not to screen or base studies on the rigid structure of disordered proteins, because these proteins do not exist in a fixed structure, and even a small disordered region can change the conformation, flexibility and stability of the protein. Many chemists screen the databases by using the rigid structure of the protein, not considering the flexible movement and the cryptic allosteric sites (CAS). CAS do not exist in the native state but they might be present in the transition state, being possible positions for drug targeting.
Also a coarse-grained model might be a good method to map out the transition pathway of disordered proteins transformation, being able to predict possible cryptic allosteric sites.
They mention that cognitive behavioral therapy is another useful treatment for insomnia, this therapy not always work for all patients. Finally the traditional Chinese medicine (TCM) seems to be a good potential treatment for insomnia, however is not enough evidence or being nontoxic, due to the highly ingredients extracted from herbs, they suggest that more clinical studies are required. Further studies and research is needed for identifying a novel highly folded protein, related with the clock complex or the sleep related receptors.

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