Rational design of allosteric modulators of the aromatase enzyme: An unprecedented therapeutic strategy to fight breast cancer.

6533b86dfe1ef96bd12c977a

RESEARCH PRODUCT

Rational design of allosteric modulators of the aromatase enzyme: An unprecedented therapeutic strategy to fight breast cancer.

Federico Berti Marzia Pennati Nadia Zaffaroni Silvia Martini Giorgio Colombo Jacopo Sgrignani Angelo Spinello Matic Pavlin Alessandra Magistrato Giovanni Grazioso

subject

Molecular dynamic medicine.drug_class In silico Allosteric regulation Cytochromes P450; Aromatase; Molecular dynamics; Aromatase inhibitors; Docking; Breast cancer; Resistance onset; Mixed inhibition mechanism Antineoplastic Agents Breast Neoplasms Molecular dynamics Molecular Dynamics Simulation Docking Structure-Activity Relationship Breast cancer Breast cancer Aromatase Allosteric Regulation Cell Line Tumor Drug Discovery medicine Resistance onset Humans Mixed inhibition mechanism Aromatase Enzyme Inhibitors Cell Proliferation Pharmacology chemistry.chemical_classification biology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Rational design Aromatase inhibitor General Medicine medicine.disease Enzyme Aromatase inhibitors Settore CHIM/03 - Chimica Generale E Inorganica Estrogen Docking (molecular)Drug Design biology.protein Cancer research Drug Screening Assays Antitumor Cytochromes P450

description

Estrogens play a key role in cellular proliferation of estrogen-receptor-positive (ER+) breast cancers (BCs). Suppression of estrogen production by competitive inhibitors of the enzyme aromatase (AIs) is currently one of the most effective therapies against ER + BC. Yet, the development of acquired resistance, after prolonged treatments with AIs, represents a clinical major concern. Serendipitous findings indicate that aromatase may be non-competitively inhibited by clinically employed drugs and/or industrial chemicals. Here, by performing in silico screening on two putative allosteric sites, molecular dynamics and free energy simulations, supported by enzymatic and cell-based assays, we identified five leads inhibiting the enzyme via a non-active site-directed mechanism. This study provides new compelling evidences for the existence of an allosteric regulation of aromatase and for the possibility of exploiting it to modulate estrogens biosynthesis. Such modulation can aptly reduce side effects caused by the complete estrogen deprivation therapy, and, possibly, delay/avoid the onset of resistance. (C) 2019 Elsevier Masson SAS. All rights reserved.

year	journal	country	edition	language
2019-01-01	European journal of medicinal chemistry

10.1016/j.ejmech.2019.02.045 https://pubmed.ncbi.nlm.nih.gov/30822713