Identification of dietary compounds that interact with the circadian clock machinery: Molecular docking and structural similarity analysis

The molecular clock is vital for regulating circadian rhythms in various physiological processes, and its dysregulation is associated with multiple diseases. As such, the use of small molecule modulators to regulate the molecular clock presents a promising therapeutic approach. In this study, we generated a homology model of the human circadian locomotor output cycles kaput (CLOCK) protein to evaluate its ligand binding sites. Using molecular docking, we obtained further insights into the binding mode of the control compound CLK8 and explored a selection of dietary compounds. Our investigation of dietary compounds was guided by their potential interactions with the retinoic acid-related orphan receptors RORα/γ, which are involved in circadian regulation. Through the molecular similarity and docking analyses, we identified oleanolic acid demethyl, 3-epi-lupeol, and taraxasterol as potential ROR-interacting compounds. These compounds may exert therapeutic effects through their modulation of RORα/γ activity and subsequently influence the molecular clock. Overall, our study highlights the potential of small molecule modulators in regulating the molecular clock and the importance of exploring dietary compounds as a source of such modulators. Our findings also provide insights into the binding mechanisms of CLK8 and shed light on potential compounds that can interact with RORs to regulate the molecular clock. Future investigations could focus on validating the efficacy of these compounds in modulating the molecular clock and their potential use as therapeutic agents.