Nuclear receptors (NRs) are important biological macromolecular transcription factors that are implicated in multiple biological pathways and may interact with other xenobiotics that are endocrine disruptors present in the environment. Examples of important NRs include the androgen receptor (AR), estrogen receptors (ER), and the pregnane X receptor (PXR). In this study we have utilized the Ligand Activity by Surface Similarity Order (LASSO) method, a ligand-based virtual screening strategy to derive structural (surface/shape) molecular features used to generate predictive models of biomolecular activity for AR, ER, and PXR. For PXR, twenty-five models were built using between 8 to 128 agonists and tested using 3000, 8000, and 24,000 drug-like decoys including PXR inactive compounds . Preliminary studies with AR and ER using LASSO suggested the utility of this approach with 2-fold enrichment factors at 20%. We found that models with 64–128 PXR actives provided enrichment factors of 10-fold (10% actives in the top 1% of compounds screened). The LASSO models for AR and ER have been deployed and are freely available online, and they represent a ligand-based prediction method for putative NR activity of compounds in this database. 1. Introduction The nuclear receptor (NRs) family of transcription factors are important targets for therapeutic interventions for multiple diseases [1] and also may interact with other xenobiotics that are endocrine disruptors present in the environment [2]. It is therefore important to identify compounds that may specifically bind NRs and act as endocrine disruptors and develop synthetic compounds that can selectively (in a cell-type and/or tissue-selective manner) modulate NR pharmacology (reviewed in [3–9]). NRs including the androgen receptor (AR; NR3C4), estrogen receptors α and β, (ERα and ERβ; NR3A1 and NR3A2) and pregnane X receptor (PXR; NR1I2) are particularly important as both therapeutic targets and for xenobiotics to mediate off-target effects. The ERs are activated by 17β-estradiol while the AR is activated by testosterone and dihydrotestosterone and these receptors are transcriptional regulators of many genes [10] with important physiological functions [11–16]. The human PXR [17–19] similarly transcriptionally regulates genes involved in xenobiotic metabolism and excretion, as well as other cellular processes, including apoptosis [20–24]. Human PXR is a broad specificity NR, binding a wide variety of molecules [25] and the activation of this NR can cause drug-drug interactions [23]. Multiple QSAR and machine
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