An integrated computational, in vitro and metabolomics approach to the discovery of novel aromatase inhibitors with anti-breast cancer activities

A novel series of azole and pyrrole-containing pyridinylmethanamine/amide derivatives were identified by virtual screening for inhibition of aromatase. Ten molecules were found to inhibit aromatase with IC₅₀ values ranging between 0.04 and 2.31 µM, more potent than the clinical drug, exemestane (IC₅₀ = 2.40 µM). The best candidate is 3-pyridinylmethanamine 17 exhibited anticancer effects in both estrogen receptor-positive T47D (IC₅₀ = 42.90 µM) and MCF-7 (IC₅₀ = 79.43 µM) breast cancer cell lines, with no toxicity shown against non-tumoural human MRC-5 cells. A pyrrole-containing 3-pyridinylmethanamine 14 is second best with IC₅₀ = 50.02 µM against T47D cells. Treatment of 17 to the MCF-7 cells revealed decrease in phosphorylation of estrogen receptors and reduction of receptor expression, as well, reduction of 17β-estradiol and estrone, and increases in testosterone levels were detected indicating its anti-estrogenic activities. Metabolomics analysis revealed that 17 and exemestane showed similar patterns in metabolomics alteration compared to the untreated control. Molecular docking and dynamics simulations predicted that hydrophobic interactions are most important for aromatase inhibition, whereas chelation activities can also contribute to inhibition. The series have drug-like profiles with acceptable toxicity, and are pharmacokinetically compatible for oral drug administration.