Abstract

Circadian rhythm is an important mechanism that controls behavior and biochemical events based on 24 h rhythmicity. Ample evidence indicates disturbance of this mechanism is associated with different diseases such as cancer, mood disorders, and familial delayed phase sleep disorder. Therefore, drug discovery studies have been initiated using high throughput screening. Recently the crystal structures of core clock proteins (CLOCK/BMAL1, Cryptochromes (CRY), Periods), responsible for generating circadian rhythm, have been solved. Availability of structures makes amenable core clock proteins to design molecules regulating their activity by using in silico approaches. In addition to that, the implementation of classification features of molecules based on their toxicity and activity will improve the accuracy of the drug discovery process. Here, we identified 171 molecules that target functional domains of a core clock protein, CRY1, using structure-based drug design methods. We experimentally determined that 115 molecules were nontoxic, and 21 molecules significantly lengthened the period of circadian rhythm in U2OS cells. We then performed a machine learning study to classify these molecules for identifying features that make them toxic and lengthen the circadian period. Decision tree classifiers (DTC) identified 13 molecular descriptors, which predict the toxicity of molecules with a mean accuracy of 79.53% using tenfold cross-validation. Gradient boosting classifiers (XGBC) identified 10 molecular descriptors that predict and increase in the circadian period length with a mean accuracy of 86.56% with tenfold cross-validation. Our results suggested that these features can be used in QSAR studies to design novel nontoxic molecules that exhibit period lengthening activity.

Highlights

  • Circadian rhythm is an important mechanism that controls behavior and biochemical events based on 24 h rhythmicity

  • Our results suggest that these molecular descriptors can be used in quantitative structure–activity relationship (QSAR) studies for the identification of nontoxic and circadian period lengthener molecules using big libraries that can be used in various CRY1 related disorders

  • CRYs are core clock proteins that participate in generating circadian rhythm by acting as strong transcriptional repressors of BMAL1/CLOCK transactivation in ­mammals[4,59,60]

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Summary

Introduction

Circadian rhythm is an important mechanism that controls behavior and biochemical events based on 24 h rhythmicity. The crystal structures of core clock proteins (CLOCK/BMAL1, Cryptochromes (CRY), Periods), responsible for generating circadian rhythm, have been solved. We performed a machine learning study to classify these molecules for identifying features that make them toxic and lengthen the circadian period. Four core clock proteins are required to generate circadian rhythm, which are BMAL1, CLOCK, CRYPTOCHROMEs (CRYs), and PERIODs (PERs). Among these BMAL1 and CLOCK form heterodimer and bind E-box on DNA (CACGTG) and in turn, initiate transcription of clock-controlled genes (CCGs) including Pers and Crys[9,10,11]. High-throughput screening is currently instrumental for identifying the molecules that affect the circadian clock

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