Computational study of drugs targeting nuclear receptors
ID Kenda, Maša (Author), ID Sollner Dolenc, Marija (Author)

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Endocrine-disrupting chemicals have been shown to interfere with the endocrine system function at the level of hormone synthesis, transport, metabolism, binding, action, and elimination. They are associated with several health problems in humans: obesity, diabetes mellitus, infertility, impaired thyroid and neuroendocrine functions, neurodevelopmental problems, and cancer are among them. As drugs are chemicals humans can be frequently exposed to for longer periods of time, special emphasis should be put on their endocrine-disrupting potential. In this study, we conducted a screen of 1046 US-approved and marketed small-molecule drugs (molecular weight between 60 and 600) for estimating their endocrine-disrupting properties. Binding affinity to 12 nuclear receptors was assessed with a molecular-docking program, Endocrine Disruptome. We identified 130 drugs with a high binding affinity to a nuclear receptor that is not their pharmacological target. In a subset of drugs with predicted high binding affinities to a nuclear receptor with Endocrine Disruptome, the positive predictive value was 0.66 when evaluated with in silico results obtained with another molecular docking program, VirtualToxLab, and 0.32 when evaluated with in vitro results from the Tox21 database. Computational screening was proven useful in prioritizing drugs for in vitro testing. We suggest that the novel interactions of drugs with nuclear receptors predicted here are further investigated.

Keywords:endocrine-disrupting chemicals, drugs, databases, nuclear receptors, molecular docking, multidimensional QSAR
Work type:Article (dk_c)
Typology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Publication status in journal:Published
Article version:Publisher's version of article
Number of pages:14 str.
Numbering:Vol. 25, iss. 7, art. 1616
ISSN on article:1420-3049
DOI:10.3390/molecules25071616 This link opens in a new window
COBISS.SI-ID:4896881 This link opens in a new window
Publication date in RUL:24.11.2021
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Record is a part of a journal

Shortened title:Molecules
COBISS.SI-ID:18462981 This link opens in a new window


License:CC BY 4.0, Creative Commons Attribution 4.0 International
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
Licensing start date:01.04.2020

Secondary language

Keywords:endokrinologija, zdravila, nuklearni receptorji, molekularno mapiranje

Document is financed by a project

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije (ARRS)
Funding programme:Young researcher grant

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije (ARRS)
Project number:P1-0208
Name:Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

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