Structure-based design and classifications of small molecules regulating the circadian rhythm period

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. Therefo...

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Autores principales:	Seref Gul, Fatih Rahim, Safak Isin, Fatma Yilmaz, Nuri Ozturk, Metin Turkay, Ibrahim Halil Kavakli
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/53751473eb374211a46f13f33d21e0bd
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spelling	oai:doaj.org-article:53751473eb374211a46f13f33d21e0bd2021-12-02T18:33:55ZStructure-based design and classifications of small molecules regulating the circadian rhythm period10.1038/s41598-021-97962-52045-2322https://doaj.org/article/53751473eb374211a46f13f33d21e0bd2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97962-5https://doaj.org/toc/2045-2322Abstract 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.Seref GulFatih RahimSafak IsinFatma YilmazNuri OzturkMetin TurkayIbrahim Halil KavakliNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Seref Gul Fatih Rahim Safak Isin Fatma Yilmaz Nuri Ozturk Metin Turkay Ibrahim Halil Kavakli Structure-based design and classifications of small molecules regulating the circadian rhythm period
description	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.
format	article
author	Seref Gul Fatih Rahim Safak Isin Fatma Yilmaz Nuri Ozturk Metin Turkay Ibrahim Halil Kavakli
author_facet	Seref Gul Fatih Rahim Safak Isin Fatma Yilmaz Nuri Ozturk Metin Turkay Ibrahim Halil Kavakli
author_sort	Seref Gul
title	Structure-based design and classifications of small molecules regulating the circadian rhythm period
title_short	Structure-based design and classifications of small molecules regulating the circadian rhythm period
title_full	Structure-based design and classifications of small molecules regulating the circadian rhythm period
title_fullStr	Structure-based design and classifications of small molecules regulating the circadian rhythm period
title_full_unstemmed	Structure-based design and classifications of small molecules regulating the circadian rhythm period
title_sort	structure-based design and classifications of small molecules regulating the circadian rhythm period
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/53751473eb374211a46f13f33d21e0bd
work_keys_str_mv	AT serefgul structurebaseddesignandclassificationsofsmallmoleculesregulatingthecircadianrhythmperiod AT fatihrahim structurebaseddesignandclassificationsofsmallmoleculesregulatingthecircadianrhythmperiod AT safakisin structurebaseddesignandclassificationsofsmallmoleculesregulatingthecircadianrhythmperiod AT fatmayilmaz structurebaseddesignandclassificationsofsmallmoleculesregulatingthecircadianrhythmperiod AT nuriozturk structurebaseddesignandclassificationsofsmallmoleculesregulatingthecircadianrhythmperiod AT metinturkay structurebaseddesignandclassificationsofsmallmoleculesregulatingthecircadianrhythmperiod AT ibrahimhalilkavakli structurebaseddesignandclassificationsofsmallmoleculesregulatingthecircadianrhythmperiod
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Structure-based design and classifications of small molecules regulating the circadian rhythm period

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