Abstract
Cytochrome P450 1A1 (CYP1A1) metabolizes estrogens, melatonin, and other key endogenous signaling molecules critical for embryonic/fetal development. The enzyme has increasing expression during pregnancy, and its inhibition or knockout increases embryonic/fetal lethality and/or developmental problems. Here, we present a virtual screening model for CYP1A1 inhibitors based on the orthosteric and predicted allosteric sites of the enzyme. Using 1001 reference compounds with CYP1A1 activity data, we optimized the decision thresholds of our model and classified the training compounds with 68.3% balanced accuracy (91.0% sensitivity and 45.7% specificity). We applied our final model to 11 known CYP1A1 orthosteric binders and related compounds, and found that our ranking of the known orthosteric binders generally agrees with the relative activity of CYP1A1 in metabolizing these compounds. We also applied the model to 22 new test compounds with unknown/unclear CYP1A1 inhibitory activity, and predicted 16 of them are CYP1A1 inhibitors. The CYP1A1 potency and modes of inhibition of these 22 compounds were experimentally determined. We confirmed that most predicted inhibitors, including drugs contraindicated during pregnancy (amiodarone, bicalutamide, cyproterone acetate, ketoconazole, and tamoxifen) and environmental agents suspected to be endocrine disruptors (bisphenol A, diethyl and dibutyl phthalates, and zearalenone), are indeed potent inhibitors of CYP1A1. Our results suggest that virtual screening may be used as a rapid tier-one method to screen for potential CYP1A1 inhibitors, and flag them out for further experimental evaluations.
Highlights
Cytochrome P450 1A1 (CYP1A1) is a highly conserved enzyme that metabolizes many xenobiotics and endogenous signaling molecules (Santes-Palacios et al 2016)
To identify potential allosteric sites based on the structure, we used a computational program—“metaPocket 2.0” that predicts potential binding sites on the protein surface based on a consensus of eight geometry- and energy-based computational methods (Zhang et al 2011); and another program—“CryptoSite” that predicts cryptic binding sites that may become apparent only after a conformational change of the protein (Cimermancic et al 2016)
We have developed a virtual screening model for CYP1A1 inhibitors based on the orthosteric site and a predicted allosteric site of the enzyme
Summary
Cytochrome P450 1A1 (CYP1A1) is a highly conserved enzyme that metabolizes many xenobiotics and endogenous signaling molecules (Santes-Palacios et al 2016). The enzyme is constitutively active in certain embryonic tissues within specific time windows during the early development of mouse (Choudhary et al 2003; Campbell et al 2005) and zebra fish (Otte et al 2010), as early as the gastrulation stage (Otte et al 2010). It has high catalytic activity for the oxidative metabolism (including 2-, 4-, 15αand 16α-hydroxylations) of female sex hormones, estradiol (E2) and estrone ( E1) (Lee et al 2003). Exogenous inhibitors of CYP1A1, including drugs or environmental agents, may disrupt important endocrine signaling processes, and lead to unintended developmental toxicity effects
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