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

VACHETTA VS ; MARDER M; ELOLA MT; TRONCOSO MF

Ciudad Autónoma de Buenos Aires

Congreso; Reunión de Sociedades de Biociencias 2020, LXV Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC), LXVIII Reunión Anual de la Sociedad Argentina de Inmunología (SAI), Reunión Anual de la Sociedad Argentina de Fisiología (SAFIS); 2020

Flavonoids are polyphenolic compounds considered potential chemopreventive candidates for cancer treatment. We previously described that the synthetic flavonoid 2?-nitroflavone (2?NF) inhibits proliferation, survival and migration of 3 human triple-negative breast cancer 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 friendliness. Prediction of Activity Spectra for Substances (PASS) web tool was used to predict 2?NF biological activities. We also 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, has high gastrointestinal absorption and penetrates the blood-brain barrier. PASS tool predicted the following activities (Pa>0.7): inhibition of hypoxia-inducible factor 1-alpha expression, kinase functions, ubiquinol-cytochrome-c reductase and aldo-keto reductase family 1 C4; enhancement of TP53 and heme oxygenase-1 expression and modulation of cytochrome P450 (CYP1A1, CYP27A1, CYP7B1, CYP2E1) and complement anaphylatoxin (C3a/C5a) receptor activities. Moreover, poly [ADP-ribose] polymerase-1, tankyrase-1 and -2, androgen receptor (AR), aryl hydrocarbon receptor (AhR), estrogen receptor (ER), CYP1A2, CYP2C9, amine oxidase [flavin-containing] A and hepatocyte nuclear factor 4- were simultaneously predicted by 3 web services as 2?NF potential targets.Thus, in silico predictions revealed that 2?NF has a favorable pharmacological profile as a drug candidate. 2?NF anti-tumoral effects might be associated with apoptosis induction, modulation of CYP activities, oxidative phosphorylation, metabolism of steroid hormones and WNT, AR, AhR and ER signaling pathways, as well as potential anti-angiogenic action.