Computational Study of Drugs Targeting Nuclear Receptors

Abstract

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.

The effect of endocrine disrupting chemicals on the vitronectin-receptor (integrin αvβ3)-mediated cell adhesion of human umbilical vein endothelial cells

“…We have previously demonstrated endocrine-disrupting potential for the tyrosine kinase inhibitor imatinib and the selective serotonin reuptake inhibitor paroxetine in silico (Kenda and Sollner Dolenc, 2020). Further, we have seen estrogenic and antithyroid activities of both imatinib and paroxetine on nuclear receptors in reporter-gene assays in vitro (Kenda, unpublished data).…”

Incomplete thermal ablation-induced up-regulation of transcription factor nuclear receptor subfamily 2, group F, member 6 (NR2F6) contributes to the rapid progression of residual liver tumor in hepatoblastoma

“…Nuclear receptors, a superfamily of transcription factors, are distributed in a variety of human tissues and organs and are widely involved in many kinds of physiological events, such as cell growth, development, and metabolism [41][42][43]. The characterization of nuclear receptors has a strong history in drug discoveries and encourages the development of precise therapy targeting these receptors for several diseases, including cancer, autoimmunity, and atherosclerosis [44][45][46]. NR2F6, a member of nuclear receptors, has been suggested to play a crucial role in several human cancers [16][17][18][19][20].…”

Triclocarban, Triclosan, Bromochlorophene, Chlorophene, and Climbazole Effects on Nuclear Receptors: An in Silico and in Vitro Study

“…Low sensitivity was observed with ED for , where in silico prediction did not match with the in vitro data for four out of five preservatives (ED predicted only one interaction with correctly (a true positive—the in silico prediction matched our in vitro result), whereas there were four false negatives—the in silico predictions falsely assigned no binding, but we observed activity in vitro ). ED was shown to have a low positive predictive value when evaluated with in vitro results in the Tox21 database ( Kenda and Sollner Dolenc 2020 ), at the expense of predicting negative results more accurately, which is useful for screening studies of chemicals ( Kolšek et al. 2014b ).…”