Exploring the selectivity of guanine scaffold in anticancer drug development by computational repurposing approach

Abstract Drug repurposing is one of the modern techniques used in the drug discovery to find out the new targets for existing drugs. Insilico methods have a major role in this approach. We used 60 FDA approved antiviral drugs reported in the last 50 years to screen against different cancer cell rece...

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Autores principales:	D. R. Sherin, T. K. Manojkumar
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d7538f1af05941f9926e109bc14cfcde
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spelling	oai:doaj.org-article:d7538f1af05941f9926e109bc14cfcde2021-12-02T18:51:00ZExploring the selectivity of guanine scaffold in anticancer drug development by computational repurposing approach10.1038/s41598-021-95507-42045-2322https://doaj.org/article/d7538f1af05941f9926e109bc14cfcde2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95507-4https://doaj.org/toc/2045-2322Abstract Drug repurposing is one of the modern techniques used in the drug discovery to find out the new targets for existing drugs. Insilico methods have a major role in this approach. We used 60 FDA approved antiviral drugs reported in the last 50 years to screen against different cancer cell receptors. The thirteen compounds selected after virtual screening are analyzed for their druggability based on ADMET parameters and found the selectivity of guanine derivatives—didanosine, entecavir, acyclovir, valganciclovir, penciclovir, ganciclovir and valacyclovir as suitable candidates. The pharmacophore model, AARR, suggested based on the common feature alignment, shows that the two fused rings as in guanine and two acceptors-one from keto-oxygen (A5) and other from the substituent attached to nitrogen of imidazole ring (A4) give the druggability to the guanine derivatives. The NBO analysis on N9 is indicative of charge distribution from the ring to substituents, which results in delocalization of negative character in most of the ligands. The molecular dynamics simulations also pointed out the importance of guanine scaffold, which stabilizes the ligands inside the binding pocket of the receptor. All these results are indicative of the selectivity of guanine scaffold in anticancer drug development, especially as PARP1 inhibitors in breast, ovarian and prostate cancer. As these seven molecules are already approved by FDA, we can safely go for further preclinical trials.D. R. SherinT. K. ManojkumarNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q D. R. Sherin T. K. Manojkumar Exploring the selectivity of guanine scaffold in anticancer drug development by computational repurposing approach
description	Abstract Drug repurposing is one of the modern techniques used in the drug discovery to find out the new targets for existing drugs. Insilico methods have a major role in this approach. We used 60 FDA approved antiviral drugs reported in the last 50 years to screen against different cancer cell receptors. The thirteen compounds selected after virtual screening are analyzed for their druggability based on ADMET parameters and found the selectivity of guanine derivatives—didanosine, entecavir, acyclovir, valganciclovir, penciclovir, ganciclovir and valacyclovir as suitable candidates. The pharmacophore model, AARR, suggested based on the common feature alignment, shows that the two fused rings as in guanine and two acceptors-one from keto-oxygen (A5) and other from the substituent attached to nitrogen of imidazole ring (A4) give the druggability to the guanine derivatives. The NBO analysis on N9 is indicative of charge distribution from the ring to substituents, which results in delocalization of negative character in most of the ligands. The molecular dynamics simulations also pointed out the importance of guanine scaffold, which stabilizes the ligands inside the binding pocket of the receptor. All these results are indicative of the selectivity of guanine scaffold in anticancer drug development, especially as PARP1 inhibitors in breast, ovarian and prostate cancer. As these seven molecules are already approved by FDA, we can safely go for further preclinical trials.
format	article
author	D. R. Sherin T. K. Manojkumar
author_facet	D. R. Sherin T. K. Manojkumar
author_sort	D. R. Sherin
title	Exploring the selectivity of guanine scaffold in anticancer drug development by computational repurposing approach
title_short	Exploring the selectivity of guanine scaffold in anticancer drug development by computational repurposing approach
title_full	Exploring the selectivity of guanine scaffold in anticancer drug development by computational repurposing approach
title_fullStr	Exploring the selectivity of guanine scaffold in anticancer drug development by computational repurposing approach
title_full_unstemmed	Exploring the selectivity of guanine scaffold in anticancer drug development by computational repurposing approach
title_sort	exploring the selectivity of guanine scaffold in anticancer drug development by computational repurposing approach
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d7538f1af05941f9926e109bc14cfcde
work_keys_str_mv	AT drsherin exploringtheselectivityofguaninescaffoldinanticancerdrugdevelopmentbycomputationalrepurposingapproach AT tkmanojkumar exploringtheselectivityofguaninescaffoldinanticancerdrugdevelopmentbycomputationalrepurposingapproach
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Exploring the selectivity of guanine scaffold in anticancer drug development by computational repurposing approach

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