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  • br Results and discussion br Conclusion In this investigatio


    Results and discussion
    Conclusion In this investigation, pharmacophore models of CK1 inhibitors were developed using a pharmacophore modeling protocol proposed by us. The optimal pharmacophore hypothesis, Hypo2, was adopted to retrieve potential CK1 inhibitors from the commercial chemical database SPECS and an in-house chemical database. Compound N6-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine was chosen from the top-ranking hits for further structural optimization since it is the smallest one and possesses a novel scaffold. A simple structural optimization, which was carried out under the guide of Hypo2, led to three active compounds with the highest one having an IC50 value of 78 nM against CK1. Collectively, this investigation reports the discovery of a lead compound targeting CK1 through a pharmacophore-based virtual screening and subsequent pharmacophore model guided structural optimization. This strategy used here could potentially be applied to the hit and lead discovery for other targets.
    Experimental section
    Introduction The field of circadian biology involves the study of Hesperadin (CRs) which are periodic behavioral and physiologic processes that cycle approximately every 24h. CRs are primarily regulated by an organism's environmental photoperiod (day/night), thus CRs likely function to synchronize critical biologic processes with light/dark cycles. It has been well established that CRs in higher organisms are generated by a master clock located in the suprachiasmatic nucleus (SCN) of the brain. The master clock synchronizes central and peripheral clocks in the body regulating numerous and diverse functions including sleep–wake cycles, hormone release, and body temperature. There is a growing body of evidence linking disrupted CRs to the pathophysiology of neuropsychiatric disease including insomnia, depression, seasonal affective disorder, and bipolar disorder.
    Description of Circadian Clock All organisms have an endogenous timing system which synchronizes biologic functions to exogenous daily cycles [1], [2]. The circadian timing system is synchronized by the action of zeitgebers (“time-givers” or synchronizers), the most powerful of which is light. In most animals, light is transduced into a circadian neural signal by specialized nonvisual cells in the retina, the melanopsin expressing retinal ganglion cells [3]. Signals from the retinal ganglion cells travel down the retinohypothalamic tract, a monosynaptic projection from the retina, which innervates a small paired structure within the hypothalamus called the SCN [4]. The SCN is comprised of about 20,000 cells and is generally accepted as the site of the master biological clock [4]. The SCN also receives input from the intergeniculate leaflet and serotonergic pathways in the brain that mediate the action of nonphotic zeitgebers on circadian cycles [1]. The time period it takes for one circadian cycle to occur is called tau (τ) and results from a core loop of translational, transcriptional, and posttranslational events in the SCN. In the absence of light and other effective zeitgebers, the molecular events that govern clock periodicity run at an endogenous rate, a condition called “free-running.” The τ for animals under free-running conditions, endogenous τ, may be less than, equal to, or greater than 24h. In mouse, endogenous τ is strain dependent and ranges from 23.3 to 23.9h [5]. In humans, endogenous τ appears to be more variable (24–25h) which may reflect difficulties in establishing true free-running conditions for people [6]. Since light cycles are the primary regulator of CRs, most animals are synchronized to a 24-h photoperiod by light resetting the timing of molecular events in the SCN on a daily basis. Mammalian genetics has played a large part in defining the components of the circadian timing system. In humans, familial advanced sleep phase syndrome (FASPS) is a disease in which patients show a daily advance in the time when they go to sleep. Genetic association studies showed that these patients carry a mutation in the protein Period2 (Per2), which removes a phosphorylation site [7]. Per2 is a member of the PAS (Per-ARNT-Sim) family of genes and is a homologue of a protein that had been identified in Drosophila as a component of the circadian clock. Per2 expression has been shown to be expressed in a pattern that oscillates with the circadian time. The link between Per2 phosphorylation and FASPS provided a link between Per protein phosphorylation and CR in mammals.