In silico prediction of potential activities and targets of the synthetic flavonoid 2'-nitroflavone

VACHETTA, VANINA; MARDER, MARIEL; ELOLA, MARÍA TERESA; TRONCOSO, MARÍA F.

BUENOS AIRES

Congreso; REUNION ANUAL BIOCIENCIAS 2020. LXV REUNION ANUAL DE SAIC; 2020

SOCIEDAD ARGENTINA DE INVESTIGACION CLINICA

Flavonoids are a group of polyphenolic compounds considered potential chemopreventive candidates for cancer treatment. One of the most aggressive subtypes of mammary tumor is triple-negative breast cancer (TNBC). We previously described that the synthetic flavonoid 2?-nitroflavone (2?NF) inhibits proliferation, survival and migration of 3 human TNBC cell lines. However, the mechanisms underlying these effects remain elusive.Here, Molinspiration and SwissADME chemoinformatics software tools were used to evaluate 2?NF pharmacokinetics, drug-likeness and medicinal chemistry. Also, Prediction of Activity Spectra for Substances (PASS) web tool was used to predict 2´NF biological activities . Moreover, we used SwissTargetPrediction, TargetNet, Random Forest QSAR, SEA and SuperPred web services for predicting 2´NF potential targets.Results from Molinspiration and SwissADME software showed that 2?NF does not violate the ?Lipinski´s rule of five? for drugs. Hence, 2?NF has high gastrointestinal absorption and penetrates the blood-brain barrier. PASS tool predicted possible activities (Pa>70%), including inhibition of hypoxia-inducible factor 1-alpha (HIF-1) expression, kinase functions, ubiquinol-cytochrome-c reductase (UQCRFS1) and aldo-keto reductase family 1 member C4 (AKR1C4), enhancement of TP53 expression, and modulation of several cytochrome P450 (CYP1A1, CYP27A1, CYP7B1) and complement anaphylatoxin receptor activities. Moreover, poly [ADP-ribose] polymerase-1 (PARP-1), tankyrase-1 (TNKS) and -2 (TNKS2), androgen receptor (AR), aryl hydrocarbon receptor (AhR), estrogen receptor (ER), cytochrome P450 1A2 (CYP1A2) and 2C9 (CYP2C9), amine oxidase [flavin-containing] A (MAO-A) and hepatocyte nuclear factor 4-alpha (HNF4A) were simultaneously predicted by three web services as 2?NF potential targets.In summary, computational predictions revealed that 2?NF has a favorable pharmacological profile as drug candidate. Anti-tumoral effects of 2?NF might be associated with induction of apoptosis, modulation of CYP activities, oxidative phosphorylation, and WNT, AR, AhR and ER signaling pathways, as well as potential anti-angiogenic action.